Treatment Strategies - Diabetes volume 5 issue 1 2013 by RBHT Library

TREATMENT STRATEGIES DIABETES

Volume 5 Issue 1

• Diabetes and Cardiovascular Risk • Glucose Monitoring • Statins • Type 1 Diabetes • Type 2 Diabetes Management

Papers include:

Continuous Glucose Monitoring: Why it is Not Enough and What Can We Expect of the Closed Loop? Martin Prázny

Enteroviral Pathogenesis of Type 1 Diabetes: A Role for Enhancing Antibodies? Enagnon Kazali Alidjinou and Didier Hober

Strategies to Mitigate the Risk of Hypoglycaemia Associated with the Treatment of Type 2 Diabetes Bo Ahrén

Obstructive Sleep Apnoea, Type 2 Diabetes and Cardiovascular Consequences Henri Tuomilehto

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E RCELONA BA

2013

Includes a Review of the 49th EASD Annual Meeting

Coming soonâ&#x20AC;Ś

IDF Europe Study on ... Access to Quality Medicines and Medical Devices for Diabetes Care in Europe In the current context of growing concerns regarding access to healthcare, and faced with the significant challenges of addressing long-term care for major chronic diseases such as diabetes, the International Diabetes Federation European Region (IDF Europe) will be publishing a study on Access to Quality Medicines and Medical Devices for Diabetes Care in Europe. This publication highlights disparities in access to quality medicines and medical devices for diabetes care in the 47 countries of the IDF Europe Region. The study aims to provide evidence to policy makers and stakeholders on the current challenges faced by people living with diabetes in terms of access to the treatment they need. While national practices do vary and comparable data may be imperfect, the study will tell a compelling story about the need for coordinated action. Providing the Evidence Currently, reliable data on the true costs of caring for people living with diabetes is scarce. The issue of having accurate and timely data on diabetes medicines and medical devices

thus needs to addressed, as currently decisions are being made in the absence of such information. Beyond the Short-term People with diabetes rely on continuous access to medicines and devices to manage their life-long condition. Most diabetes complications, such as heart disease and stroke, kidney failure and foot problems are preventable with a timely diagnosis of diabetes, effective patient and professional education, and comprehensive, multidisciplinary long-term care. This requires sufficient investment to ensure sustainable and uninterrupted access to diabetes medicines and medical devices. It is imperative that access to diabetes care be seen as an investment to promote a healthier and more productive society, and as a contributor to long-term economic growth. â&#x20AC;˘ The initial findings of the study will be released on 13 November 2013. â&#x20AC;˘ The full study will be available for download as from 4 December 2013.

For more information visit www.idf-europe.org

TREATMENT STRATEGIES DIABETES Treatment Strategies - Diabetes The Cambridge Research Centre

Welcome...

Coppergate House 16 Brune Street

I am pleased to welcome you to the latest edition of Treatment Strategies - Diabetes. In this fantastic new edition

London

we have a range of informative articles, as well as an

E1 7NJ

in-depth review of the 49th European Association for the Study of Diabetes (EASD) Meeting.

Managing Director Nigel Lloyd nigel@cambridgeresearchcentre.co.uk

The Meeting was held from 23 - 27 September, and is the

Director Yunus Bhatti

worldâ&#x20AC;&#x2122;s leading international forum for diabetes research

yunus@cambridgeresearchcentre.co.uk

for both individuals and the worldwide pharmaceutical

Publishing Director Sara Taheri sara@cambridgeresearchcentre.co.uk Chief Sub-editor Hannah Corby hannah.corby@cambridgeresearchcentre.co.uk

industry. The event was attended by over 18,000 delegates and covered a broad range of topics including type 2 diabetes, diabetes management and statins. Our review brings you all of the breaking news, research highlights, awards and products that were showcased at the event.

Filming Martin Janes video@cambridgeresearchcentre.co.uk Credit Control Manager Emma Jones emma@cambridgeresearchcentre.co.uk Accounts David Mansell

This edition also features a number of interesting and informative papers on subjects such as Type 1 diabetes, glucose monitoring and Type 2 diabetes management. With these papers we aim to bring you new insights into the latest treatment strategies for a number of different diabetic disorders. Indeed, diabetes is becoming an

Published by The Cambridge Research Centre

increasingly important area of medicine as more people

info@cambridgeresearchcentre.co.uk

are diagnosed with the disease. We hope that you enjoy

www.cambridgeresearchcentre.co.uk

the chosen content.

T: +44 (0) 20 7953 8490

Here at the Cambridge Research Centre we are always looking for new ways to bring our content to you. This year, in addition to our growing range of interactive eBooks we launched Treatment Strategies TV. Here

Printed by Printech (Europe) Limited

you will find footage from all of the most important scientific conferences, as well as interviews, symposia proceedings, roundtable events and much more. Additionally, we are excited to bring you our NewsHUB,

All information obtained by The Cambridge Research Centre and each of the contributions from various sources is as current and accurate as possible. However, due to human or mechanical errors, The Cambridge Research Centre and the contributors cannot guarantee the accuracy, adequacy or completeness of any information, and cannot be held responsible for any errors or omissions. The Cambridge Research Centre is completely independent of the review event (EASD 2013) and the use of the organisation and event hyperlink does not constitute endorsement or media partnership in any form whatsoever.

which collates important news stories, videos, blog posts and more, all in one location. The team are also all active on Twitter and LinkedIn, and please do follow us or join our LinkedIn group to find out more about our upcoming releases. I hope you enjoy this edition of Treatment Strategies - Diabetes, and please do feel free to get in contact with us and let us know your thoughts. We canâ&#x20AC;&#x2122;t wait to bring you our 2014 edition of the publication, which will feature a review of 50th EASD Meeting in Vienna. Hannah Corby, Chief Sub-editor

The Cambridge Research Centre wishes to thank the following societies for their assistance and involvement in this publication.

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Treatment Strategies - Contents

CONTENTS...

Welcome by Hannah Corby, Chief Sub-editor

Editorial Advisory Panel Listing

Foreword by Nigel lloyd, Managing Director, The Cambridge Research Centre

Congress Review Review of 49th Annual Meeting of European Association for the Study of Diabetes (EASD) Treatment Strategies was delighted to attend the 49th Annual Meeting of EASD, held in Barcelona this September. In this review, Sara Taheri brings you an in-depth overview of the event, which includes a look at the exhibition hall as well as all of the breaking news, symposia highlights, latest research and more. The review is also followed with a number of poster synopses. This is an exciting addition to the review, as the results of these studies will have a direct impact upon the future of diabetes management.

Statins and New Onset Diabetes: Getting to the Heart of the Matter - Satellite Symposium at the European Association for the Study of Diabetes (EASD) Annual Meeting, Barcelona

Diabetes and Cardiovascular Risk Obstructive Sleep Apnoea, Type 2 Diabetes and Cardiovascular Consequences Henri Tuomilehto1, 2; 1. Oivauni Sleep Clinic, Kuopio; 2. Institute of Public Health and Clinical Nutrition, University of Eastern Finland

Glucose Monitoring Continuous Glucose Monitoring: Why it is Not Enough and What Can We Expect of the Closed Loop? Martin Prazny; Third Department of Internal Medicine, First Faculty of Medicine, Prague, Czech Republic

Treatment Strategies - Diabetes

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Visit the Treatment Strategies Series online to view our eBooks, subscribe to the series and email the papers in PDF format.

Our eBooks are: • Free-to-view online • Provide an exciting interactive experience • Offer a wide range of dynamic features • Easily accessible and user friendly

View our online publications at www.cambridgeresearchcentre.co.uk

Treatment Strategies - Contents

Further Reading Glucose Monitoring Monitoring, Assessment and Control of Blood Glucose Fluctuations in Diabetes Boris Kovatchev; Department of Psychiatry and Neurobehavioural Sciences and Department of Systems and Information Engineering, Director, Center for Diabetes Technology, University of Virginia, Charlottesville, Virginia Continuous Glucose Monitoring Pratik Choudhary; Senior Lecturer and Consultant in Diabetes, Department of Diabetes, King’s College London

Type 1 Diabetes Enteroviral Pathogenesis of Type 1 Diabetes: A Role for Enhancing Antibodies? Enagnon Kazali Alidjinou and Didier Hober; Université Lille 2, Faculty of Medicine, University Hospital, Laboratory of Virology EA3610, Loos-lez-Lille

Challenges in Estimating Glomerular Filtration Rate in Diabetic Patients Marijana Vučić Lovrenčić; Department of Laboratory Medicine, Clinical Institute of Medical Biochemistry and Laboratory Medicine, Merkur Teaching Hospital, Zagreb

Type 2 Diabetes Management Strategies for Mitigating the Risk from Hypoglycaemia Associated with Diabetes Treatment Bo Ahren; Department of Clinical Sciences, Lund University, Lund

Further Reading Diabetes Management Incretins in the Management of Diabetes Santosh H Shankarnarayan and Jiten P Vora; Royal Liverpool University Hospital, Liverpool Patient Empowerment in Diabetes: Time for Returning Back to Basics? Koula Asimakopoulou, Sasha Scambler and Dave Gilbert; Senior Lecturer in Health Psychology, King’s College London, Dental Institute, Oral Health Services Research and Dental Public Health

Events Listing - Upcoming Congresses and Meetings

Further Reading Treatment and Therapeutic Strategies Future Treatments for Type 2 Diabetes Andrew J. Krentz and Marcus Hompesch; Profil Institue for Clinical Research, California Incretin Therapies in Type 2 Diabetes: The Liver Takes A Bow. Susan L. Samson; Diabetes and Endocrinology Research Center, Baylor College of Medicine, St. Luke’s Episcopal Hospital and Ben Taub General Hospital, Houston Treatment Strategies - Diabetes

Treatment Strategies - Editorial Advisory Panel

EDITORIAL ADVISORY PANEL Koula Asimakopoulou, Senior Lecturer in Health Psychology, King’s College London, Unit of Social and Behavioural Sciences, Dental Institute, London Lawrence Chan, Director, NIH-Diabetes and Endocrinology Research Center,Betty Rutherford Chair, Chief of Diabetes, Endocrinology and Metabolism, Professor of Medicine, Molecular and Cellular Biology and Biochemistry, Baylor College of Medicine, Houston Stephen Davis, Theodore E. Woodward Professor of Medicine, Chairman, Department of Medicine, University of Maryland School of Medicine, Baltimore Daniel Einhorn, Medical Director, Scripps Whittier Diabetes Institute Clinical Professor of Medicine, University of California San Diego, President, Diabetes and Endocrine Associates Carol Forsblom, FinnDiane, Clinical Coordinator, Department of Medicine, Division of Nephrology, Helsinki University Hospital Baptist Gallwitz, Vice Chair, Department of Medicine, Professor of Medicine, Outpatient Clinic for Endocrinology, Diabetes and Metabolism, University of Tübingen Magdalena Annersten Gershater, Faculty of Health and Society, Malmö University, Malmö Marit Graue, Associate Professor, Department of Public Health and Primary Health Care, University of Bergen Osama Hamdy, Adult Endocrinologist, Medical Director, Obesity Clinical Program, Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Harvard Medical School Yehuda Handelsman, Medical Director and Principal Investigator, Metabolic Institute of America, President, American Association of Clinical Endocrinologists (AACE), Los Angeles Priscilla Hollander, Endocrinologist, Baylor University Medical Center

Treatment Strategies - Diabetes

Gill Hood, NE London Diabetes Research Network Manager, Barts and The London Hospital NHS Trust Robert Knutzen, Chairman of the Board, CEO, and Co-Founder of the Pituitary Network Association (PNA), California Davida Kruger, Certified Nurse Practitioner, Henry Ford Health System, Division of Endocrinology, Diabetes, Bone and Mineral Disease, Detroit Deirdre Kyne-Grzebalski, Chairman of the Foundation of European Nurses in Diabetes Valeriya Lyssenko, Associate Professor, Department of Clinical Sciences/Diabetes and Endocrinology, Lund University, University Hospital Malmö Piero Marchetti, Dept. of Endocrinology and Metabolism, University of Pisa Juris Meier, Assistant Professor, Department of Medicine, St. Josef-Hospital; Member of the German Diabetes Association, European Association for the Study of Diabetes and American Diabetes Association Luigi Meneghini, Professor of Clinical, Division of Endocrinology, Diabetes and Metabolism Director, Kosow Diabetes Treatment Centre, Diabetes Research Institute, Miami Claudia Shwide-Slavin, Diabetes and Nutrition Private Practice, New York; American Association of Diabetes Educators (AADE) Board of Directors, American Dietetic Association Diabetes Care and Education Practice Group Dana M Small, Associate Fellow, The John B Pierce Laboratory, Associate Professor, Yale University Medical School Coen Stehouwer, Professor of Medicine, Chair, Department of Internal Medicine, Maastricht University Medical Centre Viriginia Valentine, Clinical Nurse Specialist Diabetes Network, Faculty Appointments University of New Mexico College of Nursing, School of Medicine and College of Pharmacy

including... Anne-Marie Felton, President, Foundation of European Nurses in Diabetes (FEND), Vice President, the International Diabetes Federation (IDF) Angus Forbes, Chair of Clinical Diabetes Nursing for the Foundation of European Nurses in Diabetes (FEND), Department of Primary and Intermediate Care, Florence Nightingale School of Nursing and Midwifery, Kings College London Ashley Grossman, Professor of Endocrinology, Nuffield Department of Medicine, Oxford; President, European Neuroendocrine Association

Treatment Strategies - Foreword

Foreword Nigel Lloyd Managing Director, The Cambridge Research Centre

elcome to the fifth EASD edition of Treatment

Martin Prázný’s paper ‘Continuous Glucose Monitoring: Why it

Strategies – Diabetes. In this edition we are

is not Enough and What can we Expect of the Closed Loop?’ he

excited to bring you an extensive review of

reveals that continuous glucose monitoring has become the most

the 49th Annual Meeting of EASD, which we

discussed technological advantage in diabetology in recent years.

attended in Barcelona this September. This really was a fantastic

He then discusses the problems that patients face when using

event which gave some real insights into many areas within the

continuous glucose monitoring and, using case studies, talks

field of diabetes. Our review looks back over the event, and will

about the difference that closed loop glucose monitoring can

provide you with all of the breaking news, awards and coverage

have for the diabetic patient. We have also selected some further

of the most innovative products that were showcased. A new

reading from previous editions of Treatment Strategies – Diabetes,

addition to our review is our poster synopses section, which

and please do make sure to take a look at these articles if you are

presents a selection of posters that were presented at the event.

interested in this topic.

We believe that this new feature really adds to the publication, and makes our retrospective review an even more useful tool for our readers.

Type 1 diabetes continues to be an important area of research, and in this edition we have included two papers for you on the subject. Enagnon Kazali Alidjinou and Didier Hober explore

Diabetes is a lifelong condition which has many consequences

enteroviral pathogenesis in their article ‘Enteroviral Pathogenesis

for the sufferer. Indeed, in the UK alone there are around 2.9

of Type 1 Diabetes: A Role for Enhancing Antibodies?’ Here,

million people with diabetes, and there is thought to be almost

they discuss how enteroviruses are thought to be involved

850,000 people who have undiagnosed diabetes. At EASD

in the disease pathogenesis, and they analyse the potential

2013, Type 2 diabetes was a much talked about subject area,

involvement of the facilitation of Coxsackievirus B infection

and is emerging as an important area of research, in particular

in the viral pathogenesis of Type 1 diabetes. Additionally,

how to educate young people in how to avoid developing the

Marijana Vučić Lovrenčić’s article ‘Challenges in Estimating

disease. In this edition of Treatment Strategies – Diabetes, Bo

Glomerular Filtration Rate in Diabetic Patients’, focuses upon the

Ahren discusses how to manage Type 2 diabetes in his fantastic

nephrological aspects of the disease, and writes that appropriate

article ‘Strategies to Mitigate the Risk of Hypoglycaemia

intervention at an early stage of diabetic nephropathy can

Associated with the Treatment of Type 2 Diabetes’. In this article

significantly improve the outcomes for diabetic patients. She

he discusses the negative impact which hypoglyaemia can

discusses the importance of screening for chronic kidney disease

have for diabetes patients, and the importance of selecting the

and explains more about glomerular filtration rates.

appropriate glucose-lowering medication. Indeed, by reducing the risk of hypoglycaemia, glucose lowering therapy of type 2

Finally, Henri Tuomilehto looks at how diabetes affects the

diabetes may be improved and more patients will reach their

cardiovascular system in his article ‘Obstructive Sleep Apnoea,

therapeutic target.

Type 2 Diabetes and Cardiovascular Consequences.’ Here he discusses the growing prevalence of sleep disorders, in

Glucose monitoring is very important in the prevention of

particular obstructive sleep apnoea, which has been found to

hypoglycaemia, and is a crucial device in the management

be tightly linked with Type 2 diabetes. His paper focuses on the

of diabetes as a whole. Glucose monitoring reveals individual

cardiovascular consequences that this combination of obstructive

patterns of blood glucose changes, and helps in the planning of

sleep apnoea and Type 2 diabetes has, and how they can be

meals, activities, and at what time of day to take medications. In

prevented. We have also selected some papers which also explore

Treatment Strategies - Diabetes

TREATMENT STRATEGIES SERIES Visit the publications online to view our eBooks, subscribe to the series and e-mail the papers in PDF format. Submit your papers to our forthcoming publications within the series - AIDS, Cardiology, Diabetes, Gastroenterology, Oncology, Paediatrics, Respiratory, Dermatology, Hematology and Interventional Cardiology. E-mail: editor@cambridgeresearchcentre.co.uk All articles included in Treatment Strategies are available as reprints. E-mail: reprints@cambridgeresearchcentre.co.uk Advertise your products and services within the Treatment Strategies series and appeal to todayâ&#x20AC;&#x2122;s marketplace. We provide an excellent base for advertising to targeted key audiences. E-mail: sales@cambridgeresearchcentre.co.uk

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Treatment Strategies - Meeting Review

EASD Annual Meeting 2013

23 - 27 September 2013, Barcelona 49th Annual Meeting of the European Association for the Study of Diabetes

INSIDE... The Congress Page 11. Introduction to EASD

The Exhibition Page 13. EASD Meet in Barcelona Page 14. Claude Bernard Lecture Page 15. Minkowski Prize Page 15. Albert Renold Prize and Lecture Page 16. JDRF’s Prestigious Excellence in Clinical Research Awards Page 17. Additional Results from EXAMINE Cardiovascular Safety Outcomes Trial Page 18. Type 2 Diabetes Treatment with JANUVIA® Page 18. Raising Diabetes Awareness with Super Heros Page 19. Diagnose Diabetes with In-office Testing Page 21. EndoBarrier® Therapy Efficacy Reinforced Page 22. ADAMS™ All-in-one Solution for Diabetes Testing Page 22. Diasend Promote Easy Communications Page 23. Results on Key Proteins in Insulin Sensitisers Page 24. New Technologies for Diabetes Measurement and Blood Pressure Monitoring Page 26. Pain-free Insulin Injections with Pen Needles Page 27. MyStar Extra®, the First Self-Monitoring Blood Glucose Meter with Estimated A1c Page 28. IDegLira Phase III Data shows Improved Glycaemic Control Page 29. Weight Loss combined with Dapagliflozin Contributes to Changes in Haemoglobin A1c Page 30. Omnipod Insulin Delivery System Page 31. New Developments in C-Peptide Page 32. Dulaglutide Results Show Improved Patient Health Outcomes Page 33. Tanita Body Composition Analysers Page 35. Non-invasive Glucose Monitoring Devices Page 35. Weight Loss and Caloric Modulation Page 36 Roche Personalised Diabetes Management Page 38. EFSD and Diabetes Research Programmes in Europe Page 40-48. Selected Posters

Treatment Strategies was delighted to attend the 49th Annual Meeting of EASD. In this review, Sara Taheri brings you an in-depth overview of the event, which includes a look at the exhibition hall as well as all of the breaking news, symposia highlights, latest research and more. The review is also followed with a number of poster synopses. This is an exciting addition to the review, as the results of these studies will have a direct impact upon the future of diabetes management.

The European Association for the Study of Diabetes (EASD) was founded in 1965 with the mission to encourage and support excellence in diabetes care through research and education. The EASD has been organising annual meetings since its creation, and over the years these meetings have become the largest international annual conference on diabetes research worldwide. The meetings are still driven by the academic traditions of the founding members. Although guests are welcome to attend, the chairpersons for oral presentations and poster sessions are chosen exclusively from EASD's membership. Indeed, the EASD honourary secretary is solely responsible for inviting speakers and chairpersons for symposia and lectures. The 49th EASD Annual Meeting was held in the Gran Via exhibition centre of Fira de

Barcelona, one of the biggest and most modern convention facilities in Europe. An astonishing 18,000 physicians and scientists involved in basic and clinical research in diabetes from over 120 countries attended the meeting. The most important advances in all lines of diabetes research were discussed at the event, because although millions of people suffer from diabetes mellitus, there are many aspects of the pathogenesis of diabetes in its two forms which are still unknown. The disease and its complications, including heart disease, blindness and kidney and nervous system damage are acquiring epidemic proportions at a great social and economic cost. Indeed, diabetes is a disease that greatly requires the attention of the scientific community. Since diabetes is a public health and policy matter the European Medicines

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

Agency (EMA) and the Directorate General for Research and Innovation of the European Commission were represented, to discuss the future prospects of research funding and the approval of new drugs in Europe. Patient associations also had a great presence at the meeting. Today, diabetes is considered to be a manageable health problem, with patients playing a leading role in their treatment. Indeed, patients have joined forces and assembled in associations, within which they have become actively involved in pushing health practitioners, hospitals and governments to place a greater emphasis on the human dimension of this disease. The 49th EASD provided a great meeting point for diabetologists and diabetes patients work together to improve education and patient care. Prof. Andrew J.M. Boulton, the President of the EASD, opened the meeting at the Claude Bernard Hall, welcoming the attendees. Researchers from academia and the pharmaceutical industry around the world then had the opportunity to present new developments in fields such as epidemiology, prevention, therapeutic education, health organisation, and basic and clinical research.

Treatment Strategies - Diabetes

Of the 2321 abstracts received, the Scientific Programme Committee, under the Chairmanship of Prof. Mark Walker, selected 1361 for presentation this year. All abstracts were considered anonymously and were scored by 40 referees. The Programme Committee Members designed the programme and created Oral and Poster Sessions based upon the abstracts. The scientific programme was comprised of six parallel tracks, which included inspiring symposia, keynote lectures and debates covering basic and clinical science. The scientific programme reflected the on-going efforts to understand, cure and prevent diabetes. This year the 49th EASD celebrated the 200th birthday of Claude Bernard, and named the main hall in his honour. The Association awards major prizes annually, including the Claude Bernard Medal, the Minkowski Prize and the Albert Renold Prize Lecture. The recipients of these prizes were then asked to deliver a lecture at the annual meeting. Furthermore, it was 30 years from the

inception and planning of the Diabetes Control and Complications Trial (DCCT), and the final results of the UK Prospective Diabetes Study (UKPDS) presentation, which took place at the 34th EASD annual meeting in Barcelona. In recognition of these two large landmark studies in clinical diabetology two symposia discussed new data resulting from these trials at the 49th EASD. In one symposium, which was chaired by O.B. Crofford and D.M. Nathan, the results of the CCT conducted in patients with type 1 diabetes, which established the modern management theories for this disease, was reviewed and updated. In the other, chaired by A. Adler and I.W. Campbell, the results of the UKPDS on the management of type 2 diabetes were revisited. Communication and interaction of peers, colleagues and other scientists was facilitated with the Virtual Meeting app and website. The President, Andrew J. M. Boulton, encouraged attendees to download the app and to look through the lectures and posters available on the EASD Virtual meeting website. Once again, the 49th EASD provided an excellent opportunity for attendees to communicate with peers, colleagues and other scientists both during and after the annual meeting.

Treatment Strategies - Meeting Review

EASD Meet in Barcelona Barcelona is one of the most breathtaking and exciting cities in the world, with a huge number of attractions and historical landmarks. This made it a perfect location for the 49th EASD Meeting. The "Gothic Quarter" is positioned in the centre of Barcelona's old city. Many of the buildings date back to medieval times, and some from as far back as the Roman settlement of Barcelona. Barcelona also features catalan modernista architecture, which is related to the movement known as Art Nouveau in the rest of Europe. It was developed between 1885 and1950 and left an important legacy in Barcelona. Many of these buildings are World Heritage Sites including several buildings by Antoni Gaudí, Spain's most famous architect. The city was built north of the mouth of the river Llobregat, and is surrounded by hills of granite and slate. The historical centre lies at the foot of the slate mountain Montjuïc (191 m) on which a fortress was build. South of the mountain (or hill) lies the Montjuic park. Until the 19th century this historical centre was surrounded by walls, which are still standing as the circular and rectangular avenues Rondas and Ramblas. This is both a residential and industrial areas and some parts of the city walls have been preserved. Las Rambla, the most famous street of Barcelona, is exactly 1.2 kilometres long a big tourist attraction. Laid out in 1766, it follows the contours of the medieval city walls that bounded this part of Barcelona since the 13th century. Because of its central location, the Rambla became a meeting place for all social classes. At the heart of the city lies the Plaça Sant Jaume, which has been the city’s political centre since its inception. The square is the site of the most important buildings in Barcelona and Catalonia, and the palaces of the city council (El Ayuntamiento or Casa de la Ciudad) and the province council (Palacio de la Generalidad) are located here. In Roman times the Plaza Romana or Forum was situated here, however today this is an open space in the middle of the Gothic Quarter. The Basilica of the Sagrada Família, designed by Antoní Gaudí is the most striking and still unfinished building of Barcelona. Antoni Gaudí began work on the church in 1883 but was not appointed Architect Director until 1884. The facades symbolises Birth (west), Life and Death (east) and the glorification of Christ (south). The eight towers represent the apostles. There are three entrances in the front: faith, hope and love. In the crypt is the tomb of the famous architect Gaudi, who died in 1926. This building is recognised as his bestknown work, which is still unfinished but is due to be completed by 2026. He also created remarkable buildings like Casa Batllo with ceramic roofing and Casa Mila. There are also dozens of museums including one dedicated to Picasso, another to Miró with other major arts exhibitions throughout the year and concerts and shows of different kinds happening all the time. Barcelona is almost as lively at night as it is during the day and it has a unique, exciting atmosphere, which provided attendees of the 49th EASD with a truly unforgettable experience.

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

Claude Bernard Lecture Professor Markku Laakso Awarded the Claude Bernard Prize The EASD awarded Prof. Markku Laakso the 2012 Claude Bernard Prize. The Claude Bernard Lectureship recognises contributions to the advancement of knowledge in the field of diabetes mellitus and related metabolic diseases. The Claude Bernard Prize is the most prestigious award of the EASD annual meeting, and Prof. Laakso was chosen for his outstanding contributions to the advancement of knowledge in the field of diabetes. Prof. Laakso is well recognised in the field of type 2 diabetes, genetics and cardiovascular disease. He applies a variety of approaches and methods that represent the cutting-edge of gene research methods in seeking to unravel the pathophysiology of type 2 diabetes. Prof. Laakso and his team have been exceptionally successful in linking population data with clinical patient studies and animal models, which will help to shed light on the genetic background of type 2 diabetes. The lecture was entitled ’ From one family to 10,000 men: Genes meet phenotypes in diabetes’. “One message is clear: there are also genes associated with insulin sensitivity, not just beta-cell function”. Said Prof. Laakso. He explained that the decreasing insulin production is associated with susceptibility genes, and environmental factors which then determine the demand for insulin and the development of diabetes. Prof. Markku Laakso has been Professor of Medicine at the Department of Medicine, University of Eastern Finland, Kuopio and Chief Physician of the Department of Medicine at Kuopio University Hospital since 1995. Since 2005, he has been Academy Professor at the Academy of Finland and at the University of Eastern Finland, Kuopio. He was Associate Editor for Diabetologia from 1997 to1999 and from 2008 to 2013, and a member of Editorial Board for Diabetes Care from 1997 to 1999 and for the Journal of Clinical Endocrinology and Metabolism from 2007 to 2010. His main research interests are cardiovascular complications of type 2 diabetes and genetics of insulin resistance, type 2 diabetes and cardiovascular disease. He has also received several international awards, including the Novo Nordisk Foundation Award in 2003, Castelli Pedroli Prize (the European Association for the Study of Diabetes) in 2007, and Kelly West Award (American Diabetes Association) in 2008.

Treatment Strategies - Diabetes

The EASD Commemorates Claude Bernard’s 200th Birthday This year the EASD recognised the 200th birthday of Claude Bernard, and named the main hall in his name. Claude Bernard is considered to be one of the founding fathers of modern physiology and was born on 12 July 1813 in Saint-Julien en Beaujolais in France. His findings were the basis for the understanding of metabolism. Perhaps his most famous finding was on the glycogenic function of the liver and the cause of diabetes mellitus. In 1848 he published ‘de l’origine du sucre dans l'économie animale’, where for the first time he described the production of glucose by the liver. He wrote “The digestion of carbohydrates takes place in two steps; first: transformation into glucose, second: glucose is burned in the lung. If this doesn’t happen, diabetes occurs.” He had to find sugar in the blood and look for the sugar from the vessel of the intestine where it is absorbed to find finally the place where it is burned. To investigate this he gave sweet milk soup to a dog and sacrificed the dog during digestion, he found sugar in the vena hepatica and concluded that all the glucose found in this vein resulted from the sugar the dog had eaten. For a control experiment he chose a dog that was exclusively fed with meat and like before sacrificed this animal during digestion and examined the glucose content of the vena hepatica. He found that although the dog hadn’t eaten any sugar the vena hepatica contained sugar.1 In the article “About the Origin of Sugar”, published in 18482 he summarised these findings. In this publication, he stated, “Normally there is always sugar in the blood of the heart and the liver. The sugar is formed by the liver; this is independent of the nutrition with sugar or carbohydrates.” He then looked into how or in particular in what form the sugar is stored in the liver. In February 1855, Claude Bernard isolated glycogen after numerous experiments. Throughout his life he was awarded numerous honours, including the Chair of Physiology at the University of Paris (1854), election to the Academy of Medicine (1861) and the Académie Française (1868), a Chair at the Museum of Natural History (1868), and appointment to the Senate upon the personal request of Napoléon III (1869). Claude Bernard died on February 10, 1878, aged 65, and he was accorded a public funeral, which was bestowed on a man of science for the first time in France. The European Association for the Study of Diabetes honoured Claude Bernard by dedicating a lecture in his name from 1969; the first two recipients, de Duve and Sutherland, were later awarded the Nobel Prize in physiology and medicine. References 1. Claude Bernard, de l’origine du sucre dans l'économie animale, archives générales de médicine, 1848 2. Claude Bernard, introduction à l’étude de la médecine experimentale, Paris, librairie delgrave, 1865

Treatment Strategies - Meeting Review

Minkowski Prize Miriam Cnop Awarded Minkowski Prize The European Association for the Study of Diabetes presented the Minkowski Prize for outstanding original work of a younger investigator in diabetes research. The Prize honours pathologist Oskar Minkowski (1858–1931), who determined that diabetes is caused by the suppression of pancreatic substances, which were subsequently found and identified as the hormone insulin. This was the first major breakthrough against the disease, and so he is the namesake of the Oskar Minkowski Award. The Oskar Minkowski Award has been awarded annually since 1966, and the winner is invited to pronounce a Minkowski Lecture during the EASD Annual Conference. Since 1966 the award has been sponsored by the pharmaceutical company Sanofi-Aventis. The prize consists of a certificate and 20,000 euros plus travel expenses. The candidate must be less than 45 years of age on 1st January of the year of award. Self-nomination is also possible. Miriam Cnop obtained her medical degree at the Vrije Universiteit Brussels. Training in Internal Medicine and Endocrinology, she obtained a PhD for her work on the effects of lipoproteins and free fatty acids on beta cells. She worked as a postdoctoral fellow in the laboratory of S. Kahn at the University of Washington, before joining the Endocrine Division of the Erasmus Hospital & Laboratory of Experimental Medicine, directed by D. Eizirik, at the Université Libre de Bruxelles. Her group focusses on the role of pancreatic beta cell and apoptosis in the pathogenesis of monogenic and type 2 diabetes, which aims to develop strategies to improve beta cell function and mass. They identified ER stress as a cellular response contributing to free fatty acid-induced beta cell apoptosis. Using small molecules and RNA interference strategies to modulate ER stress response and mitochondrial pathways of cell death, her team is elucidating signal transduction by which free fatty acids induce beta cell apoptosis and searches therapeutic targets to protect beta cells. They also study mutations in genes with a role in ER and mitochondrial function and have demonstrated that beta cell dysfunction and death are central in the pathogenesis of diabetes in Friedreich's ataxia, where frataxin deficiency leads to mitochondrial dysfunction. Her awards include: Endocrinology Prize by the Belgian Royal Academy of Science 2003, Belgian Novo Nordisk Prize for Diabetology 2004, EASD Rising Star 2005, Belgian Endocrine Society Award 2010, and GB Morgagni Young Investigator Award 2010. She served as Associate Editor and is member of the Advisory Board of Diabetologia.

Albert Renold Prize and Lecture Prof. Patrik Rorsman Awarded the Albert Renold Prize

The Albert Renold Prize and Lecture honours the memory of Albert Renold, the distinguished diabetologist and researcher. The lecture recognises an individual's outstanding contribution to the advancement of knowledge in the field of research on the islets of Langerhans. Albert Renold was also one of the founding fathers of EASD, serving as Honorary Secretary (19651969) and President (1974-1977). Prof. Philippe Halban chaired the 7th Albert Renold lecture on Tuesday 24th September 2013, where Prof. Patrik Rorsman presented the lecture entitled ‘The pancreatic islet: more than the sum of its parts?’ Prof. Patrik Rorsman was awarded the 2013 Albert Renold Prize Lecture. Prof. Patrik Rorsman is a Professor of Diabetic Medicine at the Oxford Centre for Diabetes, Endocrinology & Metabolism and a Medical Tutor of Harris Manchester College. Patrik Rorsman received his Medical Degree from Uppsala University in his native Sweden where, in 1986, he also received his PhD from the Department of Medical Cell Biology for his thesis Patch-clamp characterisation of pancreatic alpha and beta cells. Since 2003 he has served as Professor of Diabetic Medicine at the University of Oxford. He has published more than 200 papers dealing with the function of the pancreatic islet cells and has performed pioneering studies on the cellular and molecular regulation of pancreatic islet hormone secretion, the mechanisms that underlie the ability of the different types of islet cell (beta cells, but also alpha cells and delta cells) to sense changes in the plasma glucose concentration, and how these processes become disrupted in diabetes mellitus (T2DM). He has provided evidence that dysregulation of glucagon and somatostatin secretion contributes to islet dysfunction in T2DM and, by examining the mode of action of sulphonyureas and glucagon-like peptide 1 (GLP-1) analogues on both alpha and beta cells, he has also made important contributions to our understanding of diabetes therapy. A significant recent contribution has been his demonstration of important differences in the functional properties of human and rodent islets. His achievements have been recognised by several bodies and he has received numerous awards including the EASD Minkowski Prize in 1996. Treatment Strategies - Diabetes

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Anette-Gabriele Ziegler, M.D., Technical University of Munich

Marian Rewers, M.D., University of Colorado School of Medicine

Olli Simell, M.D., Ph.D., University of Turku

JDRFâ&#x20AC;&#x2122;s Prestigious Excellence in Clinical Research Awards Three scientists were awarded with the Excellence in Clinical Research Award at the meeting, in recognition of their important contributions toward understanding the natural history and pathogenesis of type 1 diabetes (T1D) in children. The Excellence in Clinical Research Award recognises notable clinical and translational T1D research. The award is named in honour of JDRF's International hairman, Mary Tyler Moore â&#x20AC;&#x201C; who has had T1D for over 40 years â&#x20AC;&#x201C; and her husband, S. Robert Levine, M.D., for their commitment to JDRF's efforts to find a cure for T1D and improve the lives of those living with the disease through the support of research. This year's recipients have been researching an area of T1D science that is increasing in importance, which is understanding the natural history of the disease. This understanding is key to slowing or stopping the increasing incidence among children under 14 years of age, which is estimated to rise by three percent annually worldwide. The three award winners were; AnetteGabriele Ziegler, M.D., Technical University of Munich, who led the BABYDIAB study; Marian Rewers, M.D., University of Colorado School of Medicine, who led the DAISY study; and Olli Simell, M.D., Ph.D., University of Turku, who led the DIPP study. "Drs. Ziegler, Rewers, and Simell embody the spirit of this award through their lifetime of work toward better understanding the

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cause, development, and outcomes of type 1 diabetes," say Ms. Moore and Dr. Levine. "We are proud to present this year's award to these three esteemed researchers, and are thankful for the critical insights they have contributed, and continue to contribute, helping us find the means to reverse the growing incidence and prevalence of this complex disease and create a world without type 1 diabetes." Drs. Ziegler, Rewers, and Simell followed children from birth to identify risk factors associated with T1D and the development of islet autoantibodies, the markers that indicate the activation of the autoimmune attack on insulin-producing beta cells in the pancreas. T1D occurs when these beta cells are destroyed by the immune system, rendering these patients unable to produce their own insulin. Their findings have demonstrated that the T1D disease process commonly begins in the first one to three years of life and progresses with a variable time period until the onset of T1D symptoms. Data from the three studies contributed to a larger analysis titled "Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children," published in The Journal of the American Medical Association. The global analysis revealed that nearly 70 percent of the 585 young children studied in all three countries who had two or more autoantibodies developed T1D within 10 years. The findings suggest that in certain children the disease process becomes established relatively early in life, which

means that interventions to prevent the loss of insulin independence must be instituted at an early age. "JDRF is grateful for the outstanding leadership and collaborative spirit of Drs. Ziegler, Rewers, and Simell, whose insights have helped to provide our current scientific foundation for the prevention of childhood onset type 1 diabetes," says Richard Insel, M.D., JDRF's chief scientific officer. "Their research has confirmed that type 1 diabetes is a disease process that begins long before clinical symptoms appear. Furthermore, it has defined those children at greatest risk of becoming insulin dependent in the shortest period of time, and who can benefit most from prevention therapies." The natural history studies created by Drs. Ziegler, Rewers, and Simell also helped to lay the foundation for The Environmental Determinants of Diabetes in the Young (TEDDY) study, a global consortium funded by the National Institutes of Health (NIH) that represents a comprehensive effort to identify environmental origins of T1D. TEDDY is supported through funding from the federally-funded Special Diabetes Program (SDP), which accounts for roughly one third of the federal investment in T1D research performed in the United States. Dr. Insel said, "We are thankful that these awardees continue to contribute to important type 1 diabetes research, which will be paramount in helping JDRF reach our goal of preventing the disease".

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Additional Results from EXAMINE Cardiovascular Safety Outcomes Trial Takeda, a leading contributor to innovative Type 2 diabetes treatments, presented alogliptin and fasiglifam data. The Fasiglifam Phase 3 Efficacy and Safety Data Also Presented1 Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) for the treatment of Type 2 diabetes in adults as an adjunct to diet and exercise. DPP-4is are designed to slow the inactivation of incretin hormones GLP-1 and GIP. As a result, an increased amount of active incretins enables the pancreas to secrete insulin in a glucosedependent manner, thereby assisting in the management of blood glucose levels. Data from the global EXAMINE (EXamination of CArdiovascular OutcoMes: AlogliptIN vs. Standard of CarE in Patients with Type 2 Diabetes Mellitus and Acute Coronary Syndrome) Cardiovascular (CV) safety outcomes trial indicated that alogliptin did not increase CV ischemic events including all-cause mortality (death from any cause), non-fatal myocardial infarction, non-fatal stroke, and urgent revascularisation due to unstable angina. Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) for the treatment of type 2 diabetes in adults as an adjunct to diet and exercise. Additionally, EXAMINE exploratory data presented showed rates of hospitalisation for heart failure were comparable across alogliptin and placebo groups.2 The company also presented Phase 3 data on the investigational compound fasiglifam, a potential first-in-class GPR40 agonist for the treatment of Type 2 diabetes, demonstrating the study’s primary endpoint of change from baseline in HbA1c at week 24 was met.3 Study findings showed that fasiglifam significantly improved glycaemic control with low incidence of hypoglycaemia and statistically significant reductions in HbA1c, compared with placebo, at 24 weeks in patients with type 2 diabetes inadequately controlled by diet and exercise.4 “As physicians, it is critical that we understand the impact of treating high-risk patient groups such as those evaluated by the EXAMINE trial,” said Simon Heller, D.M., EXAMINE Steering Committee member. “Many type 2 diabetes patients today are also living with cardiovascular disease, and these additional findings on heart failure hospitalisations will provide important clinical insights for physicians helping patients manage their diabetes.”

Fasiglifam Data The presentation entitled “Efficacy and safety of fasiglifam (TAK875), a GPR40 selective agonist, in Japanese type 2 diabetes mellitus patients: a Phase 3, double-blind, placebo controlled, comparative study” includes findings from the CCT-003 study, which evaluated the efficacy and safety of the investigational compound fasiglifam 25 mg and 50 mg, administered once daily before breakfast for 24 weeks, in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise.6 “We are pleased to present the Phase 3 findings from this study on fasiglifam, which further help to demonstrate the clinical profile of this potential new option for type 2 diabetes,” said Ajay Ahuja, M.D., Vice President, Global Medical Affairs, Takeda. “Takeda has built a strong foundation and maintained a robust focus in diabetes for more than 20 years, and presenting a total of seven abstracts at EASD with the scientific community underscores our dedication to addressing the needs of this growing patient population.” For more information visit; www.takeda.com

References

1. Kaku, K., Enya. K., Nakaya, R., et al. (2013). Efficacy and Safety of Fasiglifam (TAK-875), a Novel GPR40 Selective Agonist, in Japanese T2DM Patients: a Phase 3, Double-Blind, Placebo Controlled, Comparative Study Abstract. 2. White, W., Heller, S. (2013). Results from EXAMINE Study Presentation. 3. Kaku, K., Enya. K., Nakaya, R., et al. (2013). Efficacy and Safety of Fasiglifam (TAK-875), a Novel GPR40 Selective Agonist, in Japanese T2DM Patients: a Phase 3, Double-Blind, Placebo Controlled, Comparative Study Abstract. 4. Kaku, K., Enya. K., Nakaya, R., et al. (2013). Efficacy and Safety of Fasiglifam (TAK-875), a Novel GPR40 Selective Agonist, in Japanese T2DM Patients: a Phase 3, Double-Blind, Placebo Controlled, Comparative Study Abstract. 5. White, W., Heller, S. (2013). Results from EXAMINE Study Presentation. 6. Kaku, K., Enya. K., Nakaya, R., et al. (2013). Efficacy and Safety of Fasiglifam (TAK-875), a Novel GPR40 Selective Agonist, in Japanese T2DM Patients: a Phase 3, Double-Blind, Placebo Controlled, Comparative Study Abstract.

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Type 2 Diabetes Treatment with JANUVIA® MSD, Merck Sharp & Dohme presented seven new studies, including a comparison study of DPP-4 inhibition between patients with type 2 diabetes treated with JANUVIA® (sitagliptin), saxagliptin and vildagliptin. Sitagliptin is a selective, once-daily DPP-4 inhibitor that increases active GLP-1 and GIP hormones, part of the incretin system that helps regulate blood sugar.1 Sitagliptin inhibits the DPP-4 enzyme over 24 hours.1 Sitagliptin was the first approved compound in the DPP-4 inhibitor class of oral treatments, and has been approved in more than 107 countries. To date, more than 58 million prescriptions have been dispensed for the sitagliptin family of products worldwide.2

Scientific Abstracts Presented which included: Sitagliptin

- Disease Burden of Urinary Tract Infections Among Type 2 Diabetes Mellitus Patients: a US Database Study.

Medication Adherence - Meta-analysis of Studies Examining Medication Adherence to Oral Antihyperglycaemic Agents in Type 2 Diabetes.

Oxyntomodulin - Oxyntomodulin Has Significant Acute Glucoregulatory Effects Comparable to Liraglutide in Subjects With Type 2 Diabetes. - A Long-acting Oxyntomodulin Derivative Exerts Superior Body Weight Lowering to GLP1R Agonism in Monkeys.

References

1. JANUVIA Worldwide Product Circular 2012. 2. TRx Monthly May 2013.

- Comparison of Trough Dipeptidyl Peptidase-4 Inhibition in Patients With Type 2 Diabetes Treated With Saxagliptin, Sitagliptin, and Vildagliptin. - Effects of 6 Weeks Treatment With Sitagliptin on Counterregulatory and Incretin Hormones During Acute Hypoglycaemia in Patients With Type 1 Diabetes.

Burden of Urinary Tract Infection - Prevalence of Urinary Tract Infection Among Type 2 Diabetes Mellitus Patients vs. Non-diabetic Patients in Germany.

Raising Diabetes Awareness with Super Heros

Siemens Healthcare Diagnostics is raising awareness of the prevalence of diabetes among adolescents to healthcare professionals with the help of Marvel Super Hero, Iron Man. Video footage from the comic was being played over the screens at the Siemen’s stand and aims to help to promote early diagnosis and treatment to manage diabetes effectively. Diabetes testing can be delivered at the point of care via Siemens’ DCA HbA1c test kit and DCA Vantagey Analyser. “The rate of diabetes among

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adolescents is a cause for concern. We are proud to team up with Marvel’s Iron Man, a Super Hero we feel embodies our passion for innovation, to help raise awareness of the disease among young people,” states Hilda Crockett, Regional Business Manager for Point of Care at Siemens Healthcare Diagnostics. “Rapid and comprehensive diagnosis of diabetes helps clinicians to provide early intervention, and the DCA HbA1c test kit and DCA Vantage Analyser enables exactly that, whether in a GP surgery, hospital or clinic.”

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Diagnose Diabetes with In-office Testing The role of haemoglobin A1c (HbA1c) testing in the management of diabetic patients is established. More recently, the medical community has recognised its clinical utility in the disease’s diagnosis. In 2009, several major associations, including the IDF, ADA, and EASD, were part of an International Expert Committee that accepted the A1c test for diabetes diagnosis. In September 2012, the intended use for Siemens DCA® HbA1c test kit1 was expanded to include new utility as an aid to diagnose diabetes and identify patients at risk for developing the disease.

Advantages of HbA1c Testing The Expert Committees' decision was based, in part, on several advantages HbA1c testing offers when compared with the current acceptable methods of measuring glucose concentrations by fasting plasma glucose (FPG) or timed oral glucose tolerance tests (OGTT). FPG and OGTT require patients to either fast or inject a glucose beverage and have serial blood draws over three hours. Rather than relying on a single or episodic measurement of glucose levels, the HbA1c measurement represents a degree of glucose exposure over time and is more useful in guiding patient management and therapy adjustment. It is standardised and aligned to the DCCT/UKPDS study, exhibits less biologic variability and preanalytic instability, and is relatively unaffected by acute (e.g., stress or illness related) fluctuations in glucose levels.2 Independent clinical studies have shown that in-office HbA1c testing improves diabetes patient outcomes.3, 4, 5 Availability of results at the time of visit provides healthcare providers and educators with the opportunity to have meaningful, face-to-face discussions regarding treatment options. From a convenience and scheduling standpoint, it eliminates multiple visits for pre-visit blood draws or post-testing follow-up consultation.

DCA Vantage® Analyser The DCA Vantage® Analyser helps monitor glycaemic control and detect early kidney disease in environments ranging from the physician’s office to remote, point-of-care co-ordinated sites in hospitals and multisite practices. The device enables users to meet lab-

quality testing standards with an analyser that speeds and simplifies diabetes tests and delivers accurate,1 clinically relevant results shown to improve decision-making,2, 3 patient compliance, and outcomes.4 The DCA Vantage® Analyser aims to: • Manage diabetes patients more effectively. • Improve workflow in office or clinic. • Simplify management of diabetes testing in decentralised settings. • One of just two HbA1c analysers that meet NGSP performance criteria.1 • Used by three out of four physicians who perform HbA1c testing in their office.5 The device is designed to make consultations easier, and enables physicians to monitor glycaemic control and diabetes complications. Fast, actionable test results enable physicians to determine the effectiveness of a treatment plan, make therapeutic adjustments with confidence, and be more certain whether patients are complying with recommendations.

References

1 Not all product offerings are available in all countries. Not available for sale in the U.S./Kit #: 10698915. 2 Standards of Medical Care in Diabetes Diabetes Care Volume 35, Supplement 7, 1. January 2012. 3 Thaler LM, Ziemer DC, Gallina DL, et al. Diabetes in urban AfricanAmericans. XVII. Availability of rapid HbA1c measurements enhances clinical decision-making. Diabetes Care. 1999;22:1415-1421. 4 Miller CD, Barned CS, Phillips LS, et al. Rapid A1c availability improves clinical decision-making in an urban primary care clinic. Diabetes Care. 2003;26:1158-1163. 5 Cagliero E, Levina DV, Nathan DM. Immediate feedback of HbA1c levels improves glycemic control in Type 1 and insulin-treated Type 2 diabetic patients. Diabetes Care. 1999;22:1785-1789.

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Tune into the latest videos, interviews, symposium reviews, show reports and round-table discussions. Be sure to look out for our 10 postcongress videos.

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EndoBarrier® Therapy Efficacy Reinforced EndoBarrier is a breakthrough device that represents an entirely new class of non-surgical, non-pharmaceutical therapy for the treatment of type 2 diabetes and or obesity. EndoBarrier Therapy helps patients with these diseases achieve rapid and dramatic reductions in blood sugar levels, as well as substantial weight loss.

fits within the existing treatment options for type 2 diabetes and obesity. These data presented at EASD, and data from previous clinical studies, continue to demonstrate and validate the use of EndoBarrier Therapy as part of an effective type 2 diabetes treatment programme.”

EndoBarrier Therapy Oral Presentation EndoBarrier is a thin, flexible, tube-shaped liner that forms a physical barrier between ingested food and a portion of the wall of the intestine. Inserted endoscopically (through the mouth without any cutting or scarring of tissue), the EndoBarrier liner prevents the interaction of food with enzymes and hormones in the proximal intestine. In effect, food bypasses the duodenum, but without surgery or permanent changes to the anatomy. This is a convenient and discreet treatment for people whose diabetes medications are no longer effective and for those who are at risk for serious health complications and want to avoid the progression to daily insulin injections. In four presentations, GI Dynamics highlighted clinical research findings of data from two patient registries in commercialised markets, clinical research and a meta-analysis of 13 clinical studies. “Type 2 diabetes requires new treatment options that help patients achieve metabolic control, as existing options are not adequately addressing the needs of patients and physicians,” stated David Maggs, M.D., Chief Medical Officer, GI Dynamics. “There is a growing recognition among physicians worldwide of the strong impact that EndoBarrier Therapy can have and where it

During the oral presentation “Interim 12-month results from a post-market clinical trial of DJBL treatment outcomes in subjects with type 2 diabetes and/or obesity,” Dr. Julian Teare discussed health improvements achieved through EndoBarrier Therapy in 32 patients. From baseline, patients experienced a one percent decrease in HbA1c, enabling them to achieve better overall glycemic control. In addition, patients achieved a mean weight loss of 26.4 lb (11 kg), along with reductions in blood pressure, cholesterol and triglycerides.

EndoBarrier Therapy Poster Presentations Additional poster presentations on EndoBarrier Therapy that demonstrated positive treatment outcomes and utility in type 2 diabetes also featured during the meeting. These included: - Implantation of an endoscopically-deployed duodenal-jejunal bypass liner in obese type 2 diabetes subjects: 8-month follow-up of 10 subjects. - Six-month follow-up results from a registry observing DuodenalJejunal Bypass Liner treatment outcomes in subjects with type 2 diabetes and/or obesity. - Duodenal-Jejunal Bypass Sleeve for obesity and type 2 diabetes: systematic review with meta-analysis of clinical studies. “We are very pleased with the progress that we have made in our key European markets and the growing adoption of EndoBarrier Therapy by endocrinologists, as evidenced by the initiation of clinical studies by leading health authorities in France and the United Kingdom,” said Stuart A. Randle, President and Chief Executive Officer, GI Dynamics. “The data presented at EASD and the findings from these ongoing studies are designed to help further establish EndoBarrier Therapy as a standard treatment option for type 2 diabetes with local health authorities and in influential treatment guidelines.” For more information, please visit

www.gidynamics.com

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Treatment Strategies - Meeting Review

ADAMSTM All-in-one Solution for Diabetes Testing ARKRAY were displaying many of their products, and of particular interest was their Glycated Haemoglobin Analyser, ADAMS A1c HA-8180T, which is a blood glucose test meter. The ADAMS A1c, HA-8180 is a fully automated Glycohemoglobin (HbA1c) analyser based on HPLC (High Performance Liquid Chromatography). This is an all-inone solution for diabetes testing and β-thalassemia testing.

5.4 minutes or less, and in subsequent sample measurements the time taken is just 3.5 minutes. Highly accurate measurements are obtained thanks to the result of the HPLC measurement principle. The measurement result includes information of each peak and chromatogram. The results are shown in IFCC and NGSP units, which is highly effective for β-thalassemia testing. The device is equipped with a large-size colour LCD display that shows actual result, and has an easy-to-follow user interface with comments on operational procedure or informs the user about the remaining reagent volume.

The Fastest Measurement of HbA2 in the World

There are two types of HA-8180. The HA-8180V is suitable for the measurement of variant Hb and the HA-8180T is highly effective for ß-thalassemia testing.

The HA-8180T incorporates unique HPLC column technology to make it the fastest analyzer of HbA2 in the world. The time until first report is

For more information please visit:

www.arkray.co.jp

Diasend Promote Easy Communications collects and stores all diabetes patients’ data centrally, without having to install any additional software. No matter what type of device, all information is uploaded into a secure diasend.com account which is then immediately made available online. All data from multiple devices will be consolidated and presented in one report. diasend® is a cloud based system which means that uploaded data can be accessed on any device with internet access. Both patients and care providers can log on using secure accounts at diasend.com, making diabetes management easy and free up valuable resources.

Diasend were promoting their standalone system for easy uploading of information from most glucose meters, insulin pumps, CGMs and mobile apps. The diasend® System consolidates and presents information in clear and structured reports, irrelevant of the device or how the data is stored, providing information that easily shared by patients and healthcare providers. diasend® is used globally in over 15 countries including Europe, the US, Canada, Australia and New Zealand. diasend® Clinic provides a streamlined approach to disease management with its online solution for healthcare providers. This

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Having partnering with the industries top Electronic Medical Record (EMR) providers, diasend® are taking steps towards setting the standards for better care co-ordination. The EMR interface makes diabetes communications easy by aggregating data from diabetic population’s devices into the clinics’ EMR. The information from insulin pumps, glucometers, and continuous glucose monitors will be exported from diasend® to the EMR system being used. With a completely automated electronic exchange from the diasend website to EMRs, the diasend® can reduce costs by eliminating expensive administrative costs. The interface is also customisable and organisation can specify the types of reports users would like along with the time period that they would like to see them in. For more information please visit: www.diasend.com

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Results on Key Proteins in Insulin Sensitisers Metabolic Solutions Development Company, LLC (MSDC) is a drug discovery and development company investigating novel molecular targets and developing new therapeutics to treat metabolic diseases of aging, especially type 2 diabetes.

brain (which could be important in treating diseases such as Alzheimer’s and Parkinson’s disease).

On Tuesday 24th September MSDC presented data and insights into mitochondrial target of thiazolidinediones (mTOT) and its role in the development of potentially more useful and novel insulin sensitizers. The poster was entitled ‘Study of key proteins in the newly identified mitochondrial target of thiazolidinediones (mTOT): a new target for insulin sensitizers’.

Clinical studies in type 2 diabetic patients of MSDC’s investigational new drugs, MSDC-0160 and MSDC-0602, demonstrate modulating mTOT could constitute a new approach for the discovery and development of potentially more useful and novel insulin sensitisers.

Importance to the Future Discovery and Development of Anti-Diabetic Drugs

Researchers at MSDC have identified a new drug target through which insulin sensitisers exert their anti-diabetic effects. Insulin sensitisers treat the core problem in type 2 diabetes is insulin resistance, which is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin.

MSDC-0160 is a novel mTOT Modulator being developed to treat insulin resistance in patients diagnosed with type 2 diabetes. It is a once-a-day, oral insulin sensitiser that works through a newly identified mechanism of action to treat the root cause of type 2 diabetes without the side effects associated with currently marketed insulin sensitisers such as fluid retention, weight gain, and edema.

Modification of nutrient utilisation improves cell function and insulin sensitivity mTOT modulators appear to affect the regulation of biochemical pathways essential to maintaining the appropriate level of glucose, a major energy source for cells. Data suggest these new drugs have the potential to improve the body’s sensitivity to insulin, lower the percent of calorie-storing “white” fat, increase the production of calorieburning “brown” fat, preserve the function of pancreatic beta cells (which produce insulin), and protect neurons in the

MSDC-0160 works by modulating a newly defined mitochondrial target called mTOT, which stands for mitochondrial Target of Thiazolidinediones (TZDs). mTOT functions as a molecular “sensor” and “switch” connecting mitochondrial metabolism to important cellular functions are perturbed in metabolic diseases like type 2 diabetes. The new mechanism of action through which MSDC0160 selectively modulates nutrient sensing pathways, resulting in improved insulin action, lipid oxidation, generation of brown adipose tissue (brown fat), and preservation of beta cells.

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

New Technologies for Diabetes Measurement and Blood Pressure Monitoring ForaCare Suisse AG were showcasing the latest in professional diabetes measurement and consumer blood pressure monitoring technology. ForaCare are committed to improving the quality of life for diabetes patients by enhancing the ability of doctors to monitor and care for such individuals. New products launched by ForaCare at the meeting include the FORA Diamond Blood Pressure Monitor (FORA Diamond Cuff BP), the new iFORA Blood Pressure App (iFORA BP) and the new FORA COMFORT Pro GD40 blood glucose monitor with 5-Electrode Technology. FORA Diamond Cuff BP offers enhanced patient comfort and faster measurement capabilities, the new iFORA BP allows users to track their morning to night or 7/14/30 day blood pressure trends and share their progress across iOS or Android mobile devices, and the new FORA COMFORT Pro GD40 offers users the highest clinical accuracy for measurement by minimising interference from varying hematocrit levels. The FORA COMFORT Pro GD40 is recommended for hospital/ clinic settings, neonatal care, gestational diabetes care and other treatments that require tight glycemic control. Designed to offer an interactive experience, ForaCare's booth provided product demonstrations to educate EASD attendees first hand on these innovative and

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easy-to-use products. "ForaCare Suisse AG is proud to say that our demonstrations of the FORA Diamond Cuff BP were so successful that several doctors expressed an interest in purchasing a cuff directly off the floor," stated Ty-Minh Tan, CEO of ForaCare Suisse AG. "Attendees also appreciated how the iFORA app analyses trends that will empower patients to better manage their health by identifying activities that lead to glucose variations and to share and celebrate their progress over Facebook or email." ForaCare experts also explained another important feature already implemented on all FORA and FORA Diamond strips, the advanced Superior Sip In (ASSI). ASSI is an enhanced strip technology that builds upon Superior Sip In (SSI) first introduced by ForaCare in 2011. ASSI adds an additional hydrophilic layer to the blood glucose strips, making blood sip-in speed even faster, which increases glucose test precision. ForaCare is committed to the highest measuring standards and all of their monitoring devices are validated as highly accurate in the industry. FORA Blood Glucose Monitors are validated according to ISO 15197 requirements at an internationally renowned diabetes institute in Ulm, Germany. For more information, please visit www.foracare.ch

An insulin-independent way to control excess glucose. Remove it. The first highly selective SGLT2 inhibitor that removes excess glucose and its associated calories via the kidney.1

LOWERS HbA1c 1–3

with secondary benefit of weight loss*1–3

Select FORXIGA®. Effective HbA1c control and secondary benefit of weight loss for your patients with Type 2 diabetes uncontrolled on metformin.1 FORXIGA® is indicated in adults aged 18 years and older with Type 2 diabetes mellitus to improve glycaemic control as: Monotherapy – when diet and exercise alone do not provide adequate glycaemic control in patients for whom use of metformin is considered inappropriate due to intolerance. Add-on combination therapy – in combination with other glucose-lowering medicinal products including insulin, when these, together with diet and exercise, do not provide adequate glycaemic control.1 *FORXIGA® is not indicated for weight loss. SGLT2, sodium-glucose co-transporter-2.

Prescribing information can be found overleaf.

FORXIGA® 5MG & 10MG FILM-COATED TABLETS (dapagliflozin) PRESCRIBING INFORMATION. Consult Summary of Product Characteristics before prescribing. Presentation: 5mg or 10mg dapagliflozin (as propanediol monohydrate) film-coated tablets. Indications: Adults 18 years and older: For patients with type 2 diabetes mellitus to improve glycaemic control: as monotherapy when diet and exercise alone do not provide adequate glycaemic control and use of metformin is considered inappropriate due to intolerance, or in combination with other glucose lowering drugs including insulin when these, together with diet and exercise, do not provide adequate glycaemic control. Dosage: Adults: 10mg once daily as monotherapy and add-on combination therapy with other glucose lowering drugs including insulin. Forxiga can be taken at any time of day with or without food. Consider a lower dose of insulin or insulin secretagogue such as a sulphonylurea when used in combination with dapagliflozin to reduce the risk of hypoglycaemia. Children and adolescents: <18 years: Safety and efficacy not yet established. Elderly: ≥65 years: No dosage adjustment is recommended based on age. Renal function and risk of volume depletion should be taken into account. ≥75 years: Not recommended. Mild renal impairment: No dosage adjustment. Moderate & severe renal impairment: Not recommended. Severe hepatic impairment: Starting dose of 5mg is recommended, if well tolerated, dose may be increased to 10mg. Contraindications: Hypersensitivity to dapagliflozin, or excipients. Warnings and precautions: Not to be used in patients with type 1 diabetes mellitus or for diabetic ketoacidosis. Dapagliflozin is not recommended in patients concomitantly treated with pioglitazone and has not been studied with GLP-1 analogues. Use in patients with renal impairment: Not recommended in moderate to severe renal impairment (CrCl <60ml/min or eGFR <60ml/min/1.73m2). Renal function monitoring is recommended: prior to initiation of dapagliflozin and at least yearly thereafter; prior to initiation of concomitant medicinal products that may reduce renal function and periodically thereafter; for renal function approaching moderate renal impairment, at least 2 to 4 times per year. If renal function falls below CrCl <60ml/min or eGFR < 60ml/min/1.73m2, treatment should be discontinued. Use in patients with hepatic impairment: Exposure is increased in patients with severe hepatic impairment. Use in patients at risk of volume depletion, hypotension and/ or electrolyte imbalances: Dapagliflozin is associated with a modest decrease in blood pressure, which may be more pronounced in patients with very high blood glucose concentrations. Not recommended in patients receiving loop diuretics or who are volume depleted. Exercise caution in patients for whom a dapagliflozin-induced drop in blood pressure could pose a risk, such as patients with known cardiovascular disease, patients on anti-hypertensive therapy with a history of hypotension or elderly patients. Careful monitoring of volume status and electrolytes is recommended in conditions leading to volume depletion, such as acute gastrointestinal illness. In volume depleted patients temporary interruption of dapagliflozin is recommended until volume depletion is corrected. Urinary tract infections: Temporary interruption of dapagliflozin should be considered when treating pyelonephritis or urosepsis. Elderly patients: Elderly patients are more likely to have impaired renal function, be treated with medicines such as anti-hypertensives or diuretics, and be at a greater risk of volume depletion. Cardiac failure: Experience in NYHA class I-II is limited, and there is no experience in clinical studies with dapagliflozin in NYHA class III-IV. Elevated haematocrit: Caution in patients with elevated haematocrit. Urine laboratory assessments: Patients will test positive for glucose in the urine due to mechanism of action. Lactose: Not recommended in patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption. Drug interactions: Diuretics: Dapagliflozin may add to the diuretic effect of thiazide and loop diuretics and may increase the risk of dehydration and hypotension. Consider a lower dose of insulin or insulin secretagogue in combination with dapagliflozin to reduce the risk of hypoglycaemia. Dapagliflozin has a low potential for other interactions with commonly used agents in patients with type 2 diabetes. Pregnancy and lactation: Do not use during pregnancy or breast-feeding. Undesirable events: Refer to SmPC for complete information on side effects. Very common (≥1/10): Hypoglycaemia (when used with SU or insulin). Common (≥1/100 to <1/10): Vulvovaginitis, balanitis and related genital infections, urinary tract infection, back pain, dysuria, polyuria, dyslipidaemia, haematocrit increased. Legal Category: POM. Marketing authorisation number: EU/1/12/795/002 & EU/1/12/795/007 Further information is available from: Bristol-Myers Squibb / AstraZeneca EEIG, Bristol-Myers Squibb House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex, UB8 1DH, UK. [FORXIGA] is a trademark of the Bristol-Myers Squibb / AstraZeneca group of companies. Date of PI preparation: 04/2013. Approval code: 732UK13PR03937. CV 13 0047

Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard. Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd. Medical Information on 0800 731 1736 or medical.information@bms.com References: 1. FORXIGA®. Summary of product characteristics, April 2013. 2. Bailey CJ, et al. Lancet. 2010;375:2223–33. 3. Bailey CJ, et al. BMC Med 2013;11:43. 10/13 732HQ13PR09707 / 732UK13PR09847-01 / 80,004.011

Pain-free Insulin Injections with Pen Needles Pic Solution is the Artsana healthcare brand that specialises in high-quality innovative products that are designed to simplify everyday life. Pic Solution have one mission, that is to deliver effective easyto-use solutions at all times which help to improve people's quality of life, including their psychological wellbeing. Pic Solution has a range of easy-to-use, effective diabetes products delivering precision doses, featuring an exclusive pain-free top-quality needle. The entire Pic Solution diabetes range is based on innovative technologies and creative, cutting-edge solutions that guarantee outstanding quality for both therapy and in-blood glucose self-testing. Pic Solution is the only brand to offer diabetic patients the thinnest ever needles for pain-free insulin injections. The accurate triple sharpening of the tip and special treatments ensure that the needle penetrates better, minimising skin trauma and patient discomfort. 31G (with a diameter of just 0.25 mm) is in fact the thinnest needle for insulin syringes and Sensitive 32G (with a diameter of just 0.23 mm) for pen needles. These two products reflect Pic Solution’s ability to understand and resolve patients’ real needs. The new pen needles Insupen and new Insumed syringes have been tested in 8 important anti-diabetes centres in Italy. 95% of people who tried them would recommend them to another diabetic patient. Insupen pen needles have the exclusive Pic Solution needle. It is the thinnest, most pain-free Indolor needle, with an external diameter of 0.23 mm. Its thinner walls enable easier penetration and a high flow, ensuring an even more effective, painfree treatment for diabetic patients.

For more information please visit : www.picsolution.com

Treatment Strategies - Meeting Review

MyStar Extra®, the First Self-Monitoring Blood Glucose Meter with Estimated A1c At this years annual EASD meeting Sanofi presented the innovative blood glucose meter MyStar Extra®, the first self-monitoring device that demonstrate robustness and accuracy1, 2 of estimated A1c value, a key indicator for longterm glucose control..3, 4 The haemoglobin A1C (HbA1C) assay has become the cornerstone for the assessment of diabetes control and A1c test results are widely used to guide treatment decisions.5, 6 MyStar Extra® is a supportive meter designed to help people with diabetes be engaged in their insulin management and treatment plan.7-9 The estimated A1c function of MyStar Extra® is based on a new A1c estimation method tracking average glycaemia from self-monitoring data stored in the device. Scientific data presented showed that the estimation procedure used in MyStar Extra® provides accurate estimates of the long-term average blood glucose value.1, 2 “The major advantage of this method is that it can work with infrequent self-monitoring data, for example fasting blood glucose readings and occasional daily profiles, and still provide reliable estimations where other techniques could fail. In-silico studies confirmed that the dynamical estimation procedure of MyStar Extra® tracks accurately the changes in average glycemia underlying the changes in A1c,“ said Prof. Boris Kovatchev. Fasting plasma glucose (FPG) trends and a three-day FPG average provided MyStar Extra® is especially convenient for people starting on or already using insulin as

it provides additional blood glucose information on overall glucose control such as three-, seven- and thirty-day fasting plasma glucose averages and fasting plasma glucose trends. The three-day FPG average is an important parameter for insulin titration.10 Experts agree support and motivation is key to improving diabetes self-care “People with diabetes need to actively manage their diabetes to achieve good blood sugar control. Support and guidance through new technologies in self-monitoring of blood glucose can increase patients’ motivation to stay on track – and motivation is very important in a chronic disease like diabetes. What’s more, several studies have shown that ongoing feedback of one’s A1c may really help people to see the value of diabetes self-care and ultimately improve diabetes control”, said Dr. William Polonsky. At the Sanofi press briefing experts agreed that simple illustrations of therapy progress can contribute to improved diabetes care and better health outcomes for diabetics, particularly for people using insulin. “At Sanofi, our aim is to truly understand the needs of people with diabetes and to provide efficient, simple tools and guidance that help improve living with and treating diabetes”, said Pierre Chancel, Senior Vice President, Sanofi, Global Diabetes. The upcoming launches of MyStar Extra® and MyStar SylkFeel® underscore Sanofi’s commitment to provide innovations and integrated solutions to enhance diabetes self-care.”

References:

1. Kovatchev B, Flacke F, Sieber J, et al. “Accuracy of Dynamical Real-Time Estimation of A1c Using Routine Self- Monitoring Blood Glucose (SMBG) Data." Poster at EASD 2013. 2. Breton M, Flacke F, Sieber J, et al. “Robustness of Dynamical Real-Time Estimation of A1c Using Routine Self- Monitoring of Blood Glucose (SMBG) Data." Poster at EASD 2013. 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329: 977–86. 4. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998; 352: 837–53. 5. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2010; 33:S 11-61. 6. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998; 352: 837–53. 7. Data on file: MyStar Extra™ Blood Glucose Monitoring System Owner’s Guide. 8. Cagliero E, et al. Immediate feedback of HbA1c levels improves glycemic control in type 1 and insulin-treated type 2 diabetic patients. Diabetes Care 1999;22:1785–1789. 9. Fisher WA et al. What Primary Care Providers Can Do to Address Barriers to SelfMonitoring of Blood Glucose. Clinical Diabetes 2013;31(1):34-42. 10. Nathan DM, et al. Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. Diabetologia 2009;52(1):17–30. 11. Data on file: HTL-Strefa S.A. 2013.

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

IDegLira Phase III Data shows Improved Glycaemic Control IDegLira improves glycaemic control throughout the day compared to insulin degludec or liraglutide alone, with a low rate of hypoglycaemia and no weight gain compared to insulin degludec. IDegLira is a combination of Novo’s Victoza (liraglutide), a GLP-1 analogue, and Tresiba (insulin degludec) in a single-injection delivery device for type 2 diabetes. Tresiba was EU-approved in January 2013. Victoza is both US- and EU-approved. Phase 3 data from the investigational therapy IDegLira [Tresiba® (insulin degludec)/Victoza® (liraglutide injection)] were presented from the DUAL™ I trial show IDegLira demonstrates a statistically significant greater reduction in blood sugar levels HbA1c compared to insulin degludec or liraglutide alone, with no weight gain and a low rate of hypoglycaemia compared to insulin degludec in adults with type 2 diabetes. These results were also supported by data showing once-daily IDegLira provides statistically greater reductions in post-prandial glucose following all three main meals of the day (breakfast, lunch and dinner) compared to insulin degludec. IDegLira is a once-daily, single-administration basal insulin/GLP-1 analogue combination being developed for the treatment of type 2 diabetes in adults. “The efficacy of IDegLira demonstrated by the DUAL™ I data is exciting. It combines the clinical advantages, yet mitigates the principal side effects of insulin degludec and liraglutide,” said Prof. Stephen Gough, University of Oxford and Oxford University Hospitals NHS Trust, lead investigator of the study. “DUAL™ I shows how patients can achieve an average final HbA1c of 6.4% with no weight gain and a low rate of hypoglycaemia.” The DUAL™ I trial evaluated IDegLira in people with type 2 diabetes inadequately controlled on oral antidiabetic (OAD) medications compared to insulin degludec or liraglutide (1.8 mg) alone:1 - IDegLira showed a statistically significant mean HbA1c reduction of 1.9% (from baseline of 8.3%), achieving its primary endpoint of superiority versus liraglutide and non-inferiority versus insulin

Treatment Strategies - Diabetes

degludec (-1.3% and -1.4%, p<0.0001, respectively). - 81% of patients treated with IDegLira reached the HbA1c goal of <7%, and 70% reached ≤6.5% versus liraglutide alone (60% and 41%, respectively) and insulin degludec alone (65% and 48% respectively). - IDegLira resulted in a mean weight reduction of -0.5 kg and a 32% lower rate of confirmed hypoglycaemia versus insulin degludec (p<0.0001; 1.8 versus 2.6 events per patient per year) whereas liraglutide was associated with less hypoglycaemia and greater weight reduction. The effects of IDegLira on fasting and postprandial glucose levels resulted in a substantial overall improvement in glycaemic control as compared to its individual components.2 IDegLira reduced the postprandial increments significantly more than insulin degludec following all three main meals. The reduction in postprandial increments seen for IDegLira and liraglutide were similar.2 Furthermore, IDegLira resulted in significantly better control of postprandial blood glucose following a standardised mixed meal compared to insulin degludec.3 The most frequently reported adverse events seen with IDegLira in the DUAL™ I trial are consistent with its individual components.

References

1. Gough SCL, et al. IDegLira, a Novel Fixed Ratio Combination of Insulin Degludec and Liraglutide, is Efficacious and Safe in Subjects with Type 2 Diabetes: A Large, Randomized Phase 3 Trial. Oral presentation (OP 37) at the 49th Annual European Association for the Study of Diabetes (EASD) Congress, 27 September 2013. 2. Buse JB, et al. Postprandial glycaemic control following a fixed ratio combination of insulin degludec and liraglutide compared to each component individually in patients with T2D. Poster presentation (PS 084) at the 49th Annual European Association for the Study of Diabetes (EASD) Congress, 26 September 2013. 3. Holst JJ, et al. A novel fixed ratio combination of insulin degludec and liraglutide improves postprandial glycaemic control in patients with T2D: results from a standardized meal test. Poster presentation (PS 070) at the 49th Annual European Association for the Study of Diabetes (EASD) Congress, 25 September 2013.

Treatment Strategies - Meeting Review

Weight Loss Combined with Dapagliflozin Contributes to Changes in Haemoglobin A1c regression modelling to determine the contribution to the changes in HbA1c and blood pressure that were directly related to the dapagliflozininduced weight loss. This analysis included covariates (gender; baseline age, smoking, anti-hypertensive medicine, HbA1c, estimated glomerular filtration rate, weight, and SBP and DBP); study assignment; treatment; and possible treatment interactions. Three dependent variables were determined, with beta values for per-kg weight changes as HbA1c 0.028% (P< .0001), SBP 0.606 mm Hg (P< .0001), and DBP 0.253 mm Hg (P< .0001). For HbA1c, for example, overall weight losses of 3 kg and 5 kg would contribute to 8% and 13%, respectively, of the total reduction in HbA1c upon dapagliflozin treatment. Similarly, for SBP, these weight losses would contribute to 37% and 49%, respectively, and for DBP, 32% and 44%, respectively, of the total reduction in blood pressures upon dapagliflozin treatment. AstraZeneca and Bristol-Myers Squibb presented results on Dapagliflozin and weight loss. According to the results of a pooled analysis weight loss With Dapagliflozin contributes to changes in haemoglobin A1c and blood pressure for patients with type 2 diabetes. “Weight loss is actually a very powerful tool when it comes to reducing cardiovascular risk factors, and SGLT2 [sodium-glucose transporter 2] inhibition seems to be a good help on the way to achieve these weight losses,” stated lead author C. David Sjöström, MD, PhD, AstraZeneca, Mölndal, Sweden. "Dapagliflozin causes a continuous loss of calories through the kidney during treatment, providing a retained weight loss over time", he added. Dr. Sjöström and colleagues pooled data from 7 phase-3 studies that included patients who underwent both dapagliflozin monotherapy and combination therapy (dapagliflozin with metformin, sulphonylurea, thiazolidinedione, insulin; n = 1,066). The placebo pool included 988 patients.

“There is an added benefit of weight loss during dapagliflozin treatment that contributes to the overall changes in HbA1c and blood pressure levels after 24 weeks of treatment,” Dr. Sjöström concluded. Baseline characteristics showed that just under 50% of subjects were male, and had an overall mean age of 55 to 56 years, duration of type 2 diabetes of 6.3 years, weight of 88.4 kg, body mass index of 31.8, HbA1c of 8.3%, and SBP/DBP of 130.5/79.5 mmHg. The majority of patients with type 2 diabetes are overweight or obese, and it is known that weight loss can improve glycaemic control, lipid profile and blood pressure; guidelines recommend weight loss.

Across the pooled studies, the adjusted mean changes from baseline over 24 weeks demonstrated the expected benefits of dapagliflozin. The change in HbA1c with placebo (-0.60%) was significantly improved with dapagliflozin (-1.10%). Similarly, systolic blood pressure (SBP) and diastolic BP showed significant improvements over placebo with dapagliflozin (-3.68 mmHg, -1.79 mmHg). This was paralleled by a significant -2.02 kg weight loss over placebo for dapagliflozin. The researchers carried out adjusted linear

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

Omnipod, a Continuous Insulin Delivery System Ypsomed, distributor of the Omnipod and other diabetes care products under the brand Mylife Diabetescare in Europe, were displaying devices including the new smaller OmniPods that began shipping earlier this year. With no tubes, no bulky device and no regimented schedules, the OmniPod makes managing diabetes easy. The tubing-free OmniPod is now even smaller, lighter and more discreet than ever. The OmniPod® Insulin Management System is an innovative continuous insulin delivery system that provides all of the proven benefits of continuous subcutaneous insulin infusion (CSII) therapy in a way no conventional insulin pump can. The System’s innovative design and features allows the patients to live their life and manage diabetes with unprecedented freedom, comfort, convenience, and ease. The long-term health benefits of better blood glucose control are wellknown. Maintaining near-normal blood glucose levels can help you live a longer, healthier life with fewer diabetes- related complications. The OmniPod System also has many practical, everyday benefits, including convenience, freedom, flexibility, and ease of use. Continuous insulin delivery most closely mimics the insulin release of a healthy pancreas. Since the landmark 10-year Diabetes Control and Complications Trial (DCCT), the long-term health benefits of maintaining near-normal blood glucose levels have been widely recognised. Continuous insulin delivery at preset rates eliminates the need for injections and the interruptions that come with them. In addition, with the OmniPod System, insulin delivery can be changed with the press of a button to adapt to snacks or unexpected changes in daily routine.

Treatment Strategies - Diabetes

The OmniPod System is a great option for people with diabetes who require insulin, working much like the pancreas of a person without diabetes by delivering insulin in two ways: • A small, constant, background supply of insulin (called a basal rate) is delivered automatically at a programmed rate, throughout the day and night. • An extra dose of insulin (called a bolus) can be delivered when needed to match the carbohydrates in a meal or snack or to correct a high blood glucose. Wearing an insulin pump like the OmniPod offers some distinct benefits over managing diabetes with daily injections. For the body, it’s more like insulin delivery from a healthy pancreas. Patients can achieve tighter blood glucose control and improve your A1C – without needing to add injections. For more information visit: www.myomnipod.com

Treatment Strategies - Meeting Review

For more information, visit www.cebix.com.

New Developments in C-Peptide for Treating Diabetic Peripheral Neuropathy At the 49th EASD Annual Meeting Cebix Incorporated chaired a symposium on ‘C-Peptide and the Pathophysiology of Diabetes – New Developments’. On Monday 23rd September Cebix executive Dr. John Wahren, and Dr. Nigel Brunskill from the Department of Infection, Immunity and Inflammation at the University of Leicester chaired the symposium in which the latest developments on C-Peptide and the Pathophysiology of Diabetes were discussed. Cebix is focused on the treatment of diabetic complications including those affecting the function of nerves, kidneys, and eyes. Cebix's candidate drug Ersatta™ is a long-acting form of C-peptide, a naturally-occurring peptide that is formed when insulin is cleaved from pro-insulin. In healthy individuals, C-peptide and insulin are co-secreted by the beta cells in the pancreas. Type 1 diabetes is characterised by the body’s inability to produce pro-insulin and consequently both insulin and C-peptide. Because C-peptide deficiency has only recently been implicated in vascular microcirculation dysfunction, treatment for type 1 diabetes is currently limited to intensive insulin therapy and frequent blood glucose monitoring to optimise glycaemic control. Type 1 and some type 2 diabetic patients have a C-peptide deficiency, which can cause a reduction in microvascular circulation, resulting in progressive damage to the nerves, retina and kidneys. Ersatta™ is a disease-modifying replacement peptide for the treatment of complications associated with diabetes. Ersatta is a long-acting form of C-peptide that has the potential to reduce the chronic complications of diabetes, including progressive damage to the nerves, kidneys, and retina.

Cebix has been granted fast track status by FDA for Ersatta for treating diabetic peripheral neuropathy. Cebix have recently completed a 72-subject phase 1/2 clinical trial evaluating Ersatta in patients with type 1 diabetes. The trial validated Ersatta’s benign safety profile and once weekly administration, and provided favourable initial results in improved nerve conduction velocity (a measure of peripheral neuropathy). Cebix has launched an international 240-subject phase 2b trial in early 2013 measuring nerve conduction velocity as the primary endpoint. While Ersatta is initially being developed for peripheral neuropathy, the drug has potential in autonomic neuropathy, retinopathy, nephropathy, and erectile dysfunction, all long-term complications seen in both type 1 and type 2 diabetic patients. Dr. Kwon-Soo Ha began the symposium with a presentation entitled ‘C-peptide prevents development of diabetic complications by inhibiting ROSmediated intracellular events’. This was followed by a presentation on ‘C-peptide regulated pathways adapting beta cells to stress’ by Dr. Patrizia Luppi, who was followed by Dr. Sumia Essid’s presentation entitled ‘Reversal of statin-induced myopathy by C- peptide’. Gina Yosten went on to present on "Searching for the C-peptide receptor" and the Biophysical properties and molecular interactions of C-peptide were discusse by Dr. Mikael Landreh. Dr. Alexander Chibalin discussed the C-peptide mediated intracellular signalling and new findings of this in his presentation, and the lhe last presentation of the symposium was entitled ‘Development and early findings for a long-acting C-peptide,’ which was given by Dr. Joel Martin.

For more information, visit www.cebix.com

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

Dulaglutide Results Show Improved Patient Health Outcomes Eli Lilly and Company presented Phase III clinical trial data for Dulaglutide In addition to reductions in HbA1c (hemoglobin A1c) levels and weight at 26 and 52 weeks with dulaglutide,1 dulaglutidetreated patients reported significant, positive improvements compared to baseline across several patient-reported indicators of diabetes management, including: - Satisfaction with treatment and rates of perceived hyperglycaemia as measured by the Diabetes Treatment Satisfaction Questionnaire (DTSQ); - Weight-related self-perception (Impact of Weight on Self-Perception (IW-SP) and Ability to Perform Physical Activities of Daily Living Questionnaires (APPADL)); and - Perceived current health status (EuroQoL 5-Dimension Questionnaire (EQ-5D)).2 "Patients' perception of how diabetes treatment may affect their lives is an important consideration when choosing a medication. We are pleased that in this study, patients treated with dulaglutide reported improvements in several patient- reported outcome measures," said Gwen Krivi, Ph.D., Vice President, Lilly Diabetes product development. "These results, coupled with dulaglutide's positive clinical data, suggest that, if approved, our investigational once-weekly GLP-1 may be an attractive treatment option for patients with type 2 diabetes."

Treatment Strategies - Diabetes

The patient-reported outcomes from the AWARD-1 trial, a randomised, 52-week, placebo-controlled comparison of the effects of dulaglutide and exenatide twice-daily on glycaemic control in patients with type 2 diabetes on metformin and pioglitazone. The primary objective of the study was to evaluate whether dulaglutide, dosed onceweekly, was superior to placebo in reducing HbA1c from baseline at 26 weeks. Clinical results from the AWARD-1 trial showed that treatment with dulaglutide led to improvements in HbA1c levels and weight reductions.1 Dulaglutide-treated patients also demonstrated significant improvements compared to baseline and exenatide twice-daily in perceived hyperglycaemia scores (using DTSQ) at 26 and 52 weeks.2

Treatment with dulaglutide, as well as with exenatide twice-daily, led to significant improvements in perceptions of current health status (EQ-5D) compared to baseline at 26 weeks; these improvements with dulaglutide as well as exenatide twice-daily were also significant compared to placebo. Significant improvements were also seen compared to baseline at one year, with no significant differences between dulaglutide and exenatide twice-daily. Dulaglutide is one of several diabetes molecules in Lilly's late-stage pipeline, with a number of potential medicines in development for diabetes and its related conditions. Lilly expects to submit dulaglutide to regulatory authorities in 2013. References

1. Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide versus placebo and exenatide in Patients in the study noted significant type 2 diabetes (AWARD-1). Abstract #919. Presented improvements in weight-related selfat the 49th European Association for the Study of Diabetes (EASD) Annual Meeting. 23-27 September perception (IW-SP) compared to baseline at 2013, Barcelona, Spain. 26 weeks, which persisted through one year 2. Van Brunt K, Reaney M, Yu M, et al. Patient-reported of treatment. These improvements were not outcomes with dulaglutide, exenatide, or placebo th significantly different between all treatment (AWARD-1) Abstract #985. Presented at the 49 European Association for the Study of Diabetes groups.2 There were no significant differences (EASD) Annual Meeting. 23-27 September in the ability to perform physical activities 2013, Barcelona, Spain.

of daily living (APPADL) between dulaglutide-treated patients compared to baseline, placebo or exenatidetreated patients.2

Treatment Strategies - Meeting Review

Tanita Presents Body Composition Analysers Tanita is a world leader in the field of Precision Electronic Scales and Body Composition Analysers. An ethical healthcare product manufacturer, their objective is to research and bring to market technologies that facilitate health monitoring, both for professionals and for the health-conscious public. Extensive research has been carried out to establish the relationship between excess body fat, heart disease, diabetes and certain cancers; Tanita introduced the world’s first Integrated Body Fat Scale to medical research professionals in 1992. Using this same technology, Tanita then developed the world’s first Body Fat Monitor Scale for personal use in 1994.

and fitness experts worldwide. Today, Tanita continues to lead the way in the scale category for both its personal and professional models. Recent innovations include being the first to market with ‘segmental body composition analysis’ differentiating between fat and muscle in each limb - and an impressive array of radio wireless products that employ ANT+, Bluetooth and Wi-Fi protocols for remote monitoring and trend analysis.

With the mission to help people enjoy healthier lives, they have become the world leader in this area and have set the gold standard for Bio-electrical Impedance Analysis (BIA) scales and monitors. Backed by extensive clinical research and a Medical Advisory Board of independent researchers and consultants, its products are trusted by physicians, clinicians and health

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A healthy lifestyle reduces the risk of developing diabetes and its complications. It is also essential for diabetes management and care.

world diabetes day 14 November

TREATMENT STRATEGIES HEALTHCARE PUBLISHER

Visit the publications online and view in our eBook format Submit manuscripts to editor@cambridgeresearchcentre.co.uk Advertise your products and services within the Treatment Strategies series and appeal to todayâ&#x20AC;&#x2122;s marketplace All articles included in Treatment Strategies are available as reprints

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Treatment Strategies - Meeting Review

Non-invasive Glucose Monitoring Devices The developer of the GlucoTrack® model DF-F non-invasive blood glucose measurement device Integrity Applications, Inc, presented and exhibited at the 2013 EASD meeting. Integrity Applications is a medical device company focused on the design, development and commercialisation of non-invasive glucose monitoring devices for use by people with diabetes. Integrity Applications have developed the GlucoTrack model DF-F non-invasive glucose monitoring device, which is designed to help people with diabetes obtain blood glucose level measurements without the pain, inconvenience, incremental cost, and difficulty of conventional (invasive) spot finger stick devices.

Officer of Integrity Applications, presented a poster titled "Presenting a Truly Non-invasive Glucose Monitor for Home Use" on Thursday, 26 th September in a conference session titled "New Devices for Glucose Monitoring and Insulin Delivery."

The company exhibited its CE Marked GlucoTrack® model DF-F non-invasive glucose monitoring device, designed for spot measuring, at the event.

Mr. Gal said, "Attendance at EASD is vital for every company involved in the development of new technology intended to help patients with diabetes. We are eager to take this opportunity to present our GlucoTrack® DF-F blood glucose monitoring device to the distinguished attendees of this meeting, and we look forward to detailing its features and benefits to them in person."

In addition, Avner Gal, Chief Executive

For more information please visit www.integrity-app.com

Weight Loss and Caloric Modulation Arena Pharmaceuticals presented phase 3 clinical trial data for BELVIQ® (lorcaserin HCl) at the 49th EASD Annual Meeting which were focused on discovering, developing and commercialising novel drugs that target G protein-coupled receptors, or GPCRs, to address unmet medical needs. Arena Pharmaceuticals presented a poster entitled ‘Weight Loss and Caloric Modulation’. The poster looked at Lorcaserin HCl Phase 3 Trials in Obese and Overweight Patients. Lorcaserin helps overweight people with type 2 diabetes lose weight. It has serotonergic properties and acts as an anorectic. It has been approved by the US Food and Drug Administration for chronic weight management, and is available by prescription

in the United States. Lorcaserin is believed to decrease food consumption and promote satiety by selectively activating serotonin 2C receptors in the brain though the exact mechanism of action is not known.

For more information visit www.arenapharm.com Treatment Strategies - Diabetes

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Personalised Diabetes Management with Roche Roche Diabetes Care held a symposium entitled ‘Personalised Diabetes Management - the Journey to More Efficient and Effective Solutions’, which was chaired by Antonio Ceriello, Hans DeVries, and Rolf Hinzmann on Monday 23rd September. The Symposium consisted of five presentations on the following topics; Information matters – translating glucose data into clinical value; Continuous glucose monitoring – clinical applications for high performance sensors; Expand the options – insulin dosing and delivery; Use the data – reality, opportunities, and future options of mobile health; Act and react – a structured feedback loop involving patients and healthcare providers. Dr. Matthias Axel Schweitzer, Roche Diabetes Care Mannheim, Germany, gave the first presentation entitled ‘Information matters – translating glucose data into clinical value’, in which he discussed the diabetic patients need for glucose information in order to manage the daily tasks of their progressing, chronic disease. He explained that this information serves as a foundation for the patient’s use of available tools, services, and medical devices. Although evidence suggests that these can be applied successfully, he highlighted that they must be tailored to meet individual medical needs, patient wishes, and the abilities of both the healthcare team and the patients themselves. Dr. Schweitzer then explained that using glucose information to personalise diabetes management in a convenient, effective, and progressively automated, eliminates the burden of diabetes therapy and improves its quality, making this an increasingly promising reality in the treatment of diabetes. ‘Continuous glucose monitoring – clinical applications for high performance sensors’ was the title of the following presentation given by Dr. J. Hans DeVries from the Academic Medical Center, University of Amsterdam, The Netherlands. In his presentation Dr. J. Hans DeVries discussed how continuous glucose monitoring has been demonstrated to improve glucose

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control by reducing the number of hyperglycaemic and hypoglycaemic events alike in type 1 diabetes. He cited a recent meta-analysis1 which showed a meaningful reduction in HbA1c depending on baseline HbA1c and frequency of sensor use. The first report for which has been recently received showing a decrease in severe hypoglycaemia in patients who are unaware of their blood glucose levels without measuring. This should spur more widespread reimbursement across the globe. With further improvements in accuracy, which was also recently reported,2 continuous glucose monitoring is now coming of age. Dr. Iain Cranston, from the Queen Alexandra Hospitalin Portsmouth, UK, followed on with a presentation entitled ‘Expand the options – insulin dosing and delivery’. Dr Cranston explained that over recent years there has been much research published on continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) and the drive towards “closed loop care”. Nevertheless, it remains the case that the great majority of individuals with type 1 diabetes manage the disease using flexible dose multiple daily injections (MDI) and selfmonitoring of blood glucose (SMBG) levels to guide decision-making. To improve outcomes for individuals on multiple daily injection (MDI) therapy, Dr. Cranston suggested that it is necessary to improve the way SMBG data is utilised so that it is a more effective advisory processes for flexible insulin-dosing MDI regimens. In particular Dr. Cranston spoke of the impact of bolus advisory meter use in structured care programmes, with reference to the recently published ABACUS3 data. This presentation was followed by ‘Use

the Data – Reality, Opportunities, and Future Options of Mobile Health’ by Dr. Irl B. Hirsch, Professor of Medicine, University of Washington, USA. Dr. Hirsch started his presentation with the evolution of diabetes data monitoring technology over the years. He discussed how these devices were used to assess the reliability of the patient’s written logbooks, and then went on to explain that over time, glucose meter downloads have become more sophisticated, with powerful analysis allowing both clinicians and patients to recognise patterns which are not appreciated with the traditional pen and paper approach. Despite these advancements, Dr. Hirsch explained that unfortunately the barriers to downloading meters, now in addition to pumps and continuous glucose monitoring devices, has resulted in underutilisation of this technology, even in areas where computers, smart phones, and WiFi are plentiful. While the time required to utilise the tools for data download and analysis is

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considered too great for many clinicians (and patients), early studies have shown some improvement of glucose control. These trials, however, are small and non-definitive. On the other hand, clinicians who consistently use this technology to assist patients generally find it invaluable. Importantly, payers are now beginning to require some data download for a variety of reasons, including documentation of the number of strips required for individual patients. It is quite likely that payers will want to see more detailed data in the future. This last point is likely what will push this “diabetes data explosion” into the world of mobile health. Even if that is the case, “mhealth” could potentially have other downstream benefits for diabetes care. The ultimate goal is to take this relatively simple technology, which is used in everyday life, and utilise it in the world of diabetes in order to make diabetes management more efficient and to improve outcomes. Last but not least, Dr. Oliver Schnell, Forschergruppe Diabetes e.V. at the Helmholtz Center, Munich, Germany gave his presentation ‘Act and react – a structured feedback loop involving patients and healthcare providers’. Here, Dr. Schnell discussed how diabetes provides a pertinent case of chronic disease management with a particular focus on

patient self- management. Dr. Schnell explained that despite advances in diabetes therapy, many people with diabetes still fail to achieve treatment targets, thus remaining at risk of complications. He went on to describe a six-step cycle4 for personalised diabetes (self-) management and collaborative use of structured blood glucose data, which tailors therapy to individual patients and can help therapy adherence and treatment outcomes: 1. The patient receives structured education and training to perform Structured Testing. 2) Well thought-out self-monitoring of blood glucose is conducted to monitor the patient's glycaemic status. 3. Electronic devices or software tools can easily collect and document blood glucose monitoring data directly from the blood glucose meter. This can be done by the patient or by a nurse or medical assistant. This information may be stored in personal health records and viewed by patients, as well as by care providers with the consent of the patient. 4. Analysis of the data comes with a graphic presentation that illustrates the findings in an easy-to-digest manner. With increasing data, predictive modeling algorithms may be personalised to create best-fit, tailored care

models to achieve targets. 5) Treatment is chosen based on the characteristics of the individual patient and his/her self-management blood glucose profile to achieve individual treatment goals and to improve the medical outcome-and thus quality of life for the patient. 6) Treatment efficacy should be assessed on a regular basis, approximately 3-6 months after the change in therapy has been initiated.

References 1. Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ. 2011 Jul 7;343:d3805. 2. Zschornack E, Schmid C, et al. Evaluation of the performance of a novel system for continuous glucose monitoring. J Diabetes Sci Technol. 2013 Jul 1;7(4):815-23. 3. Ziegler R, Cavan DA, et al. Use of an Insulin Bolus Advisor Improves Glycemic Control in Multiple Daily Insulin Injection (MDI) Therapy Patients With Suboptimal Glycemic Control: First results from the ABACUS trial. Diabetes Care published ahead of print July 30, 2013, doi:10.2337/dc13-0251. 4. Ceriello A, Barkai L, et al. Diabetes as a case study of chronic disease management with a personalized approach: the role of a structured feedback loop. Diabetes Res Clin Pract. 2012 Oct;98(1):5-10.

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EFSD and Diabetes Research Programmes in Europe To encourage diabetes research in Europe, the EASD created its own non-profit Foundation the European Foundation for the Study of Diabetes (EFSD) in 1999. The EASD executive committee is also the executive committee of EFSD, which is under the close supervision of the EASD Council and the General Assembly of the EASD. The EFSD actively supports high quality research in diabetes across Europe by liaising with both non-governmental and governmental agencies. EFSD endeavours to support research to find a cure for diabetes and associated complications, and to prevent their onset whilst

Janssen: EFSD and Janssen Programme for the Study of the Role of the Kidney in Diabetes is intended to stimulate and accelerate European research in understanding the role of the kidney in diabetes. The emphasis of the programme is on renal glucose handling and metabolism, and in particular its physiological and pathophysiological role in type 2 diabetes. EFSD and Janssen Rising Star Fellowships aim to identify promising and innovative young researchers developing research activities in Europe. Selected candidates have the opportunity to present an overview of their past and on-going research activities during a multidisciplinary research symposium at the EASD Annual Meeting. Candidates are invited by EASD to present a lecture and receive a commemorative diploma with a research fellowship of Euro 30,000 for

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also increasing awareness. The Foundation has now become a significant European funding agency for diabetes research as it strives to enhance awareness of the severity and magnitude of this disease in Europe. Together with numerous funding partners the foundation runs an increasing number of partnership programmes. The current partners of the foundation supporting the research of diabetes in Europe include; AstraZeneca / BristolMyers Squibb; Boehringer Ingelheim; Chinese Diabetes Society; Janssen; Japan Diabetes Society; Juvenile Diabetes Research Foundation; Lilly; Merck Sharp & Dohme; Novartis; Novo Nordisk and Sanofi.

their institution. Merck Sharp & Dohme: EFSD and MSD have established a European Research Programme on novel therapies for type 2 diabetes with joint funding. This programme is intended to encourage and accelerate European research to identify and get an understanding of novel therapies for the treatment of type 2 diabetes. Boehringer Ingelheim: EFSD and Boehringer Ingelheim have established a new partnership called the EFSD and Boehringer Ingelheim European Diabetes Research Programmes. These consist of two elements, each with a different focus: Regulation of Secretion and Function of Non-Insulin Peptides from the Endocrine Pancreas for basic research projects; Mechanisms Relating Renal Dysfunction to Cardiovascular Disease in

Type 2 Diabetes for clinical/translational research projects. Novartis: EFSD and Novartis have established a partnership called the EFSD/Novartis European Research Programme in Microvascular Complications of Diabetes This aims to encourage European basic and clinical research that focuses on microvascular complications of diabetes. Juvenile Diabetes Research Foundation and Novo Nordisk: EFSD, JDRF and Novo Nordisk European Programme in Type 1 Diabetes Research has been renewed, this aims to promote research targeted at finding a cure for type 1 diabetes and its complications. EFSD, JDRF and Novo Nordisk Research Fellowships in Type 1 Diabetes. The objective of this Research Fellowships is

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to support young investigators engaged in research focused on type 1 diabetes and its complications. Lilly: The EFSD/Lilly European Diabetes Research Fund was created to promote increased European diabetes research and to increase public awareness and political understanding of the magnitude and burden of the disease. EFSD/Lilly Mental Health and Diabetes Programme focuses on European research aimed at clinical research into improved care of patients with diabetes and mental diseases including all forms of depression, schizophrenia and alzheimerâ&#x20AC;&#x2122;s disease. EFSD/Lilly Research Fellowships objective is to encourage research in the field of metabolism and complications of diabetes, and to promote medical education within these areas. Chinese Diabetes Society and Lilly: EFSD, CDS and Lilly Programme focuses on collaborative research endeavours between European and Chinese research centres and/ or individual investigators. The objective of these fellowships is to provide the

opportunity for young researchers in china to visit a European institution.

which accepts applications from all fields of clinical and basic research.

AstraZeneca/Bristol-Myers Squibb: The EFSD European Diabetes Research Programme in Cellular Plasticity Underlying the Pathophysiology of Type 2 Diabetes is supported by an educational grant from AstraZeneca/Bristol-Myers Squibb. Investigations into cellular plasticity of the diabetes disease process are welcomed in this programme.

Sanofi: A new partnership, the EFSD and Sanofi European Research Programmeâ&#x20AC;&#x2122;s objective is to encourage new projects aimed at advancing current knowledge. The programme is intended to stimulate European research focusing on innovative approaches to treat type 1 and/or type 2 diabetes through an increased understanding of the underlying pathophysiological processes.

To encourage research projects aimed at advancing knowledge of macrovascular complications of diabetes EFSD together with an educational grant from AstraZeneca/Bristol-Myers Squibb has established a Clinical Diabetes Research Programme in Macrovascular Complications of Diabetes. EFSD, supported by an educational grant from AstraZeneca/Bristol-Myers Squibb has established a European Diabetes Research Programme in Patient Education to encourage projects in this area. Novo Nordisk A/S: EFSD and Novo Nordisk Partnership for Diabetes Research in Europe is a programme

EFSD and Sanofi Programme for collaborative clinical diabetes research between European and non-European countries plan is to initiate a collaboration between European clinical research in rapidly developing countries who would benefit from the collaboration with research institutes in Europe. Japan Diabetes Society: EFSD and JDS Reciprocal Travel Research Fellowships, of which there are up to four, are fellowships of Euro 50,000 each. This fellowships aims to encourage collaborative research between Europe and Japan in the field of diabetes. Applicants are accepted from Japan to travel to Europe and also from Europeans to travel to Japan.

Additionally, EFSD also runs the following programmes:

morbidity and mortality in certain cancers.

EFSD Clinical Research Grants in Diabetes is an independent programme to stimulate clinical research into all aspects of diabetes.

EFSD Albert Renold Fellowships is a programme supported by an unrestricted educational grant from Merck Sharp & Dohme (MSD). A Fellowship for Young Scientists, this programme enables young scientists to travel and stay at other institutions to learn different scientific techniques related to diabetes research. Either the home or the host institution must be based in Europe or an associated country.

EFSD New Horizons Collaborative Research Initiative, which was created to promote inter-regional collaboration in diabetes research throughout Europe and rebalance the uneven funding that has historically been distributed. EFSD Research Programme in Diabetes and Cancer aims to promote investigations to identify an association between diabetes and increased

For more information visit: www.europeandiabetesfoundation.org Treatment Strategies - Diabetes

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The Associations’ Village Exhibition Area The Associations’ Village is a special exhibition area, organised by the EASD in collaboration with IDF Europe. This provides attendees the opportunity to connect with international diabetes associations, societies and study groups exhibiting at the annual meeting. Represented association, society and study groups each had their own stand to display current activities and highlight the work and practices they are undertaking. The Associations’ Village provided a multinational networking platform with the aim to further increase and facilitate the exchange of knowledge and experiences among diabetes associations. It also aimed at providing physicians and researchers from all over the world information on the existing professional and patient associations. At the Associations’ Village visiting physicians and researchers had the opportunity to learn about diabetes in a variety of different countries, speak with colleagues and get the latest information on diabetes research from all over Europe.

Direct Scientific Exchange: EASD Poster Sessions At the Annual EASD Meeting poster presentations are thought of as equal to that of oral presentations. The posters are mounted in the morning of the first day and are displayed throughout the duration of the meeting, and are removed on the last day. For first-rate and direct scientific exchange all posters were presented at six one hour Poster Discussion Sessions which were held on Tuesday, Wednesday and Thursday from 12:30 to 14:45, when no other scientific sessions were taking place. During the Poster Presentation Sessions, the presenting author was present or if not, had made arrangements for somebody with knowledge of the displayed work to be present at the poster. Posters were also available via EASD Virtual Meeting where participants were able to discuss and comment on the posters using the Virtual Conference Tool.

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Early Phase of Metformin Action in Dietary Obese Mice: Lack of Involvement of AMP-Activated Protein Kinase and Possible Interaction with n-3 Fatty Acids P. Kucharikova, O. Horakova, M. Rossmeisl and J. Kopecky Department of Adipose Tissue Biology, Institute of Physiology Academy of Sciences of the Czech Republic v.v.i., Prague Long-chain n-3 polyunsaturated fatty acids (omega-3) of marine origin, mainly eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3), exhibit beneficial effects on health. They act as natural hypolipidaemics and they could prevent development of cardiovascular disease in humans. In mice, but not in humans, omega-3 could counteract development of insulin resistance and type 2 diabetes (T2D). We have shown previously that omega-3 prevented impairment of hepatic insulin resistance in mice fed a high-fat diet (HFD), which was dependent on functional AMP-activated protein kinase (AMPK).1 Metformin (1,1-dimethylbiguanide) is the most widely prescribed drug to treat hyperglycaemia in individuals with T2D and it is recommended, in conjunction with lifestyle modifications (dietary measures, weight control and physical activity), as a first-line oral therapy. This antidiabetic drug with blood glucoselowering effect also has beneficial impact on lipid metabolism. The precise mechanism of metformin action still remains unknown. Existing data suggest that metformin lowers glycaemia via mild suppression of mitochondrial complex I activity, leading to a decrease in hepatic glucose production and concomitant AMPK activation.2, 3 However, it was shown, that metformin exhibit glucoselowering effect even in liver-specific AMPK-deficient mice.4 This suggests that AMPK-independent mechanisms of metformin action may also exist. We sought to learn whether pre-treatment of dietary obese mice with omega-3 could enhance early phase of metformin action, and whether AMPK is involved. Adult insulin resistant obese mice fed HFD for 6 weeks were randomly assigned either a HFD diet or the diet containing omega-3 concentrate replacing 15% (wt/wt) of

dietary lipids (HFD+F). At the end of this dietary intervention, which lasted for two weeks, mice were treated either with single high (400mg/kg body wt.) or low (60mg/ kg body wt.) dose of metformin or placebo (saline) by means of oral gavage and 30 minutes later on, the mice were subjected to oral glucose tolerance test (OGTT). Results showed that both omega-3 and high dose of metformin significantly decreased glucose levels 30, 45 and 60 minutes after the glucose load when compared to saline-treated mice. The incremental area under the glucose curve (AUC) in the treated mice was also significantly lower than in the control animals. Omega-3 tended to augment the metformin action, but the effect was not statistically significant. Similar results were observed in mice subjected to the low dose of metformin, which elicited a relatively weak effect on glucose tolerance, while a trend for the additive effect of metformin and omega-3 was apparent at 60 minutes following the glucose load.

response to glucose challenge, while showing a trend for additive improvements of glucose tolerance when combined with a low dose of metformin. AMPK was not essential for the acute blood glucoselowering effect of metformin.

Poster Synopsis

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Possible AMPK-independent interactions between omega-3 and metformin regarding their effects on glucose homeostasis are likely and require further characterisation. Supported by Ministry of Health of the Czech Republic (NT13763-4).

References

1. Jelenik T, Rossmeisl M, Kuda O, et al., ”AMP-activated protein kinase α2 subunit is required for the preservation of hepatic insulin sensitivity by n-3 polyunsaturated fatty acids.” Diabetes (2010), 59: pp. 2737-46 2. El-Mir MY, Nogueira V, Fontaine E, et al., ”Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I.” J Biol Chem. (2000), 275:pp. 223-8 3. Zhou G, Myers R, Li Y, et al. ”Role of AMPactivated protein kinase in mechanism of metformin action.” J Clin Invest. (2001), 108:pp. 1167-74. 4. Foretz M, Hébrard S, Leclerc J, et al., ”Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state.” J Clin Invest. (2010), 120: pp. 2355-69

Hepatic AMPK activity assessed 30 minutes after the administration of metformin (400 mg/kg body wt.) did not differ between the sub-groups. To further investigate the involvement of AMPK in metformin action, an additional experiment was performed, in which the low dose of metformin and HFD-fed mice lacking α2 subunit of AMPK (as well as Petra Kucharikova, Bc. has been their wild-type controls) were working at the Department of used. However, no effect of the Adipose Tissue Biology at The AMPK ablation on metformin Institute of Physiology Academy effect was observed. of Sciences of the Czech Republic, v.v.i., in Prague since 2011. Currently, she is finishing In conclusion, we her MSc studies at the Faculty of demonstrated acute doseScience of Charles University in dependent hypoglycaemic Prague. Her thesis is focused on insulin sensitivity and effects of both omega-3 and the effects of combined dietary and pharmacological metformin during OGTT in intervention. She will finish her MSc studies in 2014. dietary obese mice. Omega-3 lowered the glycaemic

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Poster Synopsis

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Specific Changes in Plasma Lipidome in Obesity and Type 2 Diabetes are Associated with Physical Inactivity and Muscle Mitochondrial Function T. Kurdiova1, B. Ukropcova1, M. Balaz1, G. Liebisch2, M. Vician3, M. Vlcek1, M. Srbecky4, J. Olejnik3, R. Imrich1, V. Belan4, I. Klimes1, G. Schmitz2, D. Gasperikova1 and J. Ukropec1 1.Obesity Section, Institute of Experimental Endocrinology, SAS, Bratislava; 2. University Hospital Regensburg; 3. Department of Surgery, Slovak Medical University, Bratislava; 4. Radiodiagnostic Clinic, University Hospital, Bratislava

Introduction

kg.m-2), pre-diabetic (Impaired Fasting

The world faces the pandemy of obesity and type 2 diabetes (T2D). T2D is characterised by insulin resistance at the level of many tissues, including skeletal muscle. Muscle insulin resistance and decreased muscle mitochondrial content & function1 are closely related and causally linked to a physically inactive lifestyle. Thus, regular exercise is the most powerful physiological stimulus capable of increasing both biological effect of insulin and mitochondrial content & function, promoting oxidation of lipids.2

Glucose/Impaired Glucose Tolerance) (n=24; 31.3±3.2 kg.m-2) and T2D men (n=15; 31.4±3.9 kg.m-2).

Dyslipidemia plays a central role in linking obesity to T2D. Plasma lipidome contains a broad range of different lipid species which could modify metabolism. Nevertheless, up-to-date detailed information on plasma lipidome composition, regulation and function in obesity and T2D is still scarce, although a few clinical studies point at distinct plasma lipid profile associated with metabolic disease. In our study, we investigated the interrelation of plasma lipidome with skeletal muscle mitochondrial content/ function and physical activity in middle aged lean healthy (Normal Glucose Tolerance, NGT) (n=28; 23.2±2.2 kg.m-2), overweight/obese (NGT) (n=29; 30.4±2.8

Material and Methods Volunteers underwent a complex metabolic phenotyping including the assessment of insulin sensitivity (euglycemic hyperinsulinemic clamp), glucose tolerance (oGTT), adiposity & fat distribution (MRI) and hepatic lipid content (1H-MR spectroscopy). Physical activity was monitored with accelerometers and with standardised questionnaire. Samples of m. vastus lateralis were obtained by needle biopsy and expression of peroxisome proliferators-activated receptor-gamma coactivator 1-alpha (PGC1-α) and mitochondrial DNA (mtDNA) content were determined by qRT-PCR. The activity of cytochrome C oxidase (COX) was measured by oxymetry in permeabilised muscle fibers. Plasma lipidome was analysed by mass spectroscopy.

Results

Individuals with type 2 diabetes preferred low intensity physical activity, which was clearly reflected in a significantly reduced time dedicated to moderate and high intensity physical activity, as objectively assessed by accelerometers (40% reduction Timea Kurdiova gained her Master of Science compared to lean). degree from Commenius University in Bratislava, Higher body weight Slovakia in the field of Physiology. Currently, was generally she is finishing her PhD at the Institute of Experimental Endocrinology, Slovak Academy associated with a of Sciences, Bratislava. Her major research focus decreased leisure is skeletal muscle and adipose tissue biology in time index (based obesity and T2D. on self-evaluation by a questionnaire)

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(r=-0.375, p<0.001, n=96). Similarly, diabetes was associated with a decrease in mitochondria-related parameters: (i) PGC1-α mRNA (the coordinator of mitochondrial biogenesis) (p<0.01, compared to lean), (ii) mtDNA content (the marker of mitochondrial number) (p<0.05, compared to overweight/obese NGT) and (iii) activity of mitochondrial enzyme (COX, mitochondrial function) (p<0.05, compared to overweight/obese NGT). Overall, decreased physical activity was correlated with impaired metabolic phenotype (lower insulin sensitivity, increased adiposity, hypertrophic adipocytes) and decreased PGC1-α gene expression. A complex plasma lipidomic analysis included determination of lipid species with different chain length and saturation. Most lipid species (phosphatidylcholines, cholesteryl esters, phosphatidylinositols, phosphatidylethanolamines) were upregulated in pre-diabetes and/or T2D and negatively correlated with physical activity and PGC1-α mRNA. However, a great majority of lysophosphadidylcholine (LPC) species were downregulated with pre-diabetes and diabetes and some LPCs had positive associations with physical activity, muscle PGC1-α mRNA and COX activity. Importantly, LPC 18:1 and 18:2 were found to be decreased in the metabolically healthy obese compared to lean healthy individuals, before the onset of metabolic disease (p<0.001). LPC 18:2 has recently emerged as a putative biomarker and an independent risk factor of pre-diabetes and/or T2D, predicting the impairment of glucose tolerance up to 7 years before disease onset.3, 4 In our population, LPC 18:2 was strongly

negatively correlated with several clinical phenotypes of obesity, including BMI (r=-0.73, p<0.001, n=86), adiposity (r=-0.70, p<0.001, n=83), adipocyte diameter (r=-0.57, p<0.001, n=83), fasting glycemia & insulinemia (r=-0.35, p<0.001, n=86; r=-0.36, p<0.001, n=86) and it was positively associated with insulin sensitivity (r=0.40, p<0.001, n=85).

Conclusion Type 2 diabetes is accompanied by physical inactivity, reduced muscle

mitochondrial biogenesis and function and specific changes in plasma lipidome. This suggests that physical inactivity might also contribute to the pathogenesis of T2D by regulating plasma lipid composition. Furthermore, discovery of early specific lipid biomarkers of T2D risk might help to identify individuals at high-risk for metabolic disease development, greatly increasing the chances to delay or prevent disease onset.

References 1. Patti, M.E. & Corvera, S. The role of

mitochondria in the pathogenesis of type 2 diabetes. Endocr Rev 31, 364-395 (2010). 2. Toledo, F.G. & Goodpaster, B.H. The role of weight loss and exercise in correcting skeletal muscle mitochondrial abnormalities in obesity, diabetes and aging. Mol Cell Endocrinol 379, 30-34 (2013). 3. Floegel, A., et al. Identification of serum metabolites associated with risk of type 2 diabetes using a targeted metabolomic approach. Diabetes 62, 639-648 (2013). 4. Wang-Sattler, R., et al. Novel biomarkers for pre-diabetes identified by metabolomics. Mol Syst Biol 8, 615 (2012).

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Poster Synopsis

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Poster Synopsis

Obesity and the Inflammation of Fat Tissue of Children D. Rockstroh Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, Medical Center Adiposity Diseases (IFB), Hospital for Children & Adolescents, Leipzig

Obesity is characterised by an accumulation of adipose tissue (AT) in order to store excess energy, which is associated with an increased secretion of pro-inflammatory adipokines1 and gives rise to a state of chronic, low-grade inflammation.2, 3

The Influence of Inflammatory Cells on Adipose Tissue It has previously been shown that a low-grade inflammation state is accompanied by an increase in the number of macrophages.4, 5 In general, macrophages play an important role in the immune system and tissue homeostasis by clearing pathogens and old or dead cells.6 Hirasaka et al.7 showed that an excessive infiltration of macrophage into AT worsens insulin sensitivity in rodents, whereas a decrease in the amount of macrophages leads to inhibition of obesity-induced insulin resistance.8 Recent studies have demonstrated that multiple intracellular signalling pathways are activated in adipocytes during adipocyte hypertrophy, which leads to an increased secretion of cytokines, and chemokines.9, 10, 11 So far, little is known about the alterations of macrophage recruitment at the level of adipose tissue during the ontogenic development of adipose tissue and obesity. Therefore, it is of central importance to understand the pathogenesis of obesity in children.

Macrophage Recruitment in Adipose Tissue of Children To investigate the development of obesity

in children and associated changes in AT biology, the Childhood Adipose Tissue biobank was established. Since the initiation of the project, 207 subcutaneous AT samples from 171 Caucasian children (106 lean, 16 overweight, 49 obese) who underwent selective surgery were collected. Children were 0 to 18 years old and free of severe diseases. The following exclusion criteria have been defined: type 1 or type 2 diabetes, generalised inflammation, cardiovascular or peripheral artery disease, malignant disease and genetic syndromes. Anthropometric data, including age, gender, pubertal stage, height, weight, and medical history were recorded before surgery. To investigate the occurrence of macrophages in AT from children, immunohistochemical analyses for CD68 (specific macrophages marker) were performed. Preliminary analyses indicate that macrophage recruitment already occurs in obese children. The mechanisms leading to the recruitment in the obese state are not completely understood. There is evidence that hypertrophy and local hypoxia play an important role in this setting.12 This might lead to a rupture of the plasma membrane, dilatation of the endoplasmic reticulum and release of cell contents to the extracellular space, where they evoke inflammatory responses.13-15

Heterogeneity of Macrophages

Macrophages can show a high plasticity and heterogeneity as a respond to a D. Rockstroh studied biology at the “Freie multitude of stimuli Universität Berlin” and finished with a diploma that they receive degree. She achieved her diploma thesis from their microat the Max-Planck Institute for molecular genetics Berlin. Since September 2010 she has environment.16 been working on her doctoral project, which Therefore, they can is focused upon adipose tissue development be classified into and the progression of obesity in children in pro-inflammatory order to understand obesity development and M1 and antiassociated comorbidities during childhood, adolescence and adulthood. inflammatory M2 macrophages.

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Obesity induces a phenotypic switch from an anti-inflammatory M2 polarised state to a pro-inflammatory M1 state.17 Preliminary analyses indicate that a shift in the M1/ M2 ratio on mRNA level of the previously described M1 (CD86) and M2 (CD163/ D206) markers could not be observed in children. With this project, we strive for a better understanding of how AT alterations occurring with the development of obesity in children. New therapeutic strategies, which suppress the obesity induced inflammatory response, could contribute to the prevention of type 2 diabetes and cardiovascular diseases.

Acknowledgments The authors would like to acknowledge the co-operation with the departments of orthopaedic surgery and pediatric surgery of the University Hospital Leipzig, who have made invaluable contribution to the collection of adipose tissue samples. We thank all children who participated in the studies. We gratefully appreciate the help of the nurses, technical assistants and physicians who performed the clinical examinations and data collection. This work was supported by grants from the German Research Council (DFG) for the Clinical Research Center “Obesity Mechanisms” CRC1052/1 C05 and the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1001 (IFB AdiposityDiseases ADI K7-10 and ADI K7-11 to A.K.)

References 1. Landgraf,K, Friebe,D, Ullrich,T, Kratzsch,J, Dittrich,K, Herberth,G, Adams,V, Kiess,W, Erbs,S, Körner,A: Chemerin as a Mediator between Obesity and Vascular Inflammation in Children. Journal of Clinical Endocrinology & Metabolism 97:E556-E564, 2012 2. Baker,JL, Olsen,LW, Sorensen,TI: Childhood body-mass index and the risk of coronary heart disease in adulthood.

N.Engl.J.Med. 357:2329-2337, 2007 3. Shoelson,SE, Herrero,L, Naaz,A: Obesity, inflammation, and insulin resistance. Gastroenterology. 132:21692180, 2007 4. Cancello,R, Henegar,C, Viguerie,N, Taleb,S, Poitou,C, Rouault,C, Coupaye,M, Pelloux,V, Hugol,D, Bouillot,JL, Bouloumie,A, Barbatelli,G, Cinti,S, Svensson,PA, Barsh,GS, Zucker,JD, Basdevant,A, Langin,D, Clement,K: Reduction of macrophage infiltration and chemoattractant gene expression changes in white adipose tissue of morbidly obese subjects after surgery-induced weight loss. Diabetes. 54:2277-2286, 2005 5. Weisberg,SP, McCann,D, Desai,M, Rosenbaum,M, Leibel,RL, Ferrante,AW, Jr.: Obesity is associated with macrophage accumulation in adipose tissue. J.Clin.Invest. 112:17961808, 2003 6. Weigert,A, Jennewein,C, Brune,B: The liaison between apoptotic cells and macrophages--the end programs the beginning. Biol.Chem. 390:379-

390, 2009 7. Hirasaka,K, Kohno,S, Goto,J, Furochi,H, Mawatari,K, Harada,N, Hosaka,T, Nakaya,Y, Ishidoh,K, Obata,T, Ebina,Y, Gu,H, Takeda,S, Kishi,K, Nikawa,T: Deficiency of Cbl-b gene enhances infiltration and activation of macrophages in adipose tissue and causes peripheral insulin resistance in mice. Diabetes. 56:2511-2522, 2007 8. Patsouris,D, Li,PP, Thapar,D, Chapman,J, Olefsky,JM, Neels,JG: Ablation of CD11c-positive cells normalizes insulin sensitivity in obese insulin resistant animals. Cell Metab. 8:301-309, 2008 9. Berg,AH, Scherer,PE: Adipose tissue, inflammation, and cardiovascular disease. Circ.Res. 96:939-949, 2005 10. Hotamisligil,GS: Inflammation and metabolic disorders. Nature. 444:860867, 2006 11. Schenk,S, Saberi,M, Olefsky,JM: Insulin sensitivity: modulation by nutrients and inflammation. J.Clin. Invest. 118:2992-3002, 2008 12. Skurk,T, Alberti-Huber,C, Herder,C,

Hauner,H: Relationship between adipocyte size and adipokine expression and secretion. J.Clin. Endocrinol.Metab. 92:1023-1033, 2007 13. Leist,M, Jaattela,M: Four deaths and a funeral: from caspases to alternative mechanisms. Nat.Rev.Mol.Cell Biol. 2:589-598, 2001 14. Ziegler,U, Groscurth,P: Morphological features of cell death. News Physiol Sci. 19:124-8.:124128, 2004 15. Cinti,S, Mitchell,G, Barbatelli,G, Murano,I, Ceresi,E, Faloia,E, Wang,S, Fortier,M, Greenberg,AS, Obin,MS: Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J.Lipid Res. 46:2347-2355, 2005 16. Mosser,DM, Edwards,JP: Exploring the full spectrum of macrophage activation. Nat.Rev.Immunol. 8:958-969, 2008 17. Lumeng,CN, Bodzin,JL, Saltiel,AR: Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J.Clin.Invest. 117:175-184, 2007

Treatment Strategies - Diabetes

Poster Synopsis

Treatment Strategies - Meeting Review

Poster Synopsis

Effect of Omega 3/ALA Supplementation on Inflammatory Markers and ER Stress in Diabetic Rats Maria Cristina Foss-Freitas Faculty member at the Ribeirao Preto Medical School, São Paulo University

A state of chronic and sub-clinical inflammation is often observed in diabetic patients, and more recently it has been associated with activation of the endothelium reticulum stress (ERS). Previous studies have shown

that polyunsaturated fatty acids ω3 eicosapentaenoic acid (EPA; C20:5n-3) and docosahexaenoic acid (DHA; C22:6n-3) can modulate gene expression of transcription factors

such as NFkB and PPAR, which can contribute to reduce inflammation and insulin resistance (IR) in laboratory animals, but little is known about the effect of ω3 α-linolenic acid (ALA; C18:3n-3). The ω3/ALA is the primary

fatty acid of the n-3 pathway found in seeds oils, notably those of flaxseeds and chia.

The aims of this study was to evaluate the effects of ω3/ ALA supplementation Maria Cristina Foss-Freitas has been a Faculty on sub- clinical member at the Ribeirao Preto Medical Schoolinflammatory process, São Paulo University since 2008. She finished control of glucose her specialisation in Internal Medicine and and lipid metabolism Endocrinology and Metabolism in 2001 at the same school, where she now works as a Professor and activation of ERS of Medicine. She is also engaged in clinical practice in animal models of and research on inflammation and diabetes, and is diabetes mellitus. interested in evaluating the metabolic effect of nutrients such as omega 3 and BCAA in hyperglycaemia and insulin resistance situations. We studied 40 wistar

Treatment Strategies - Diabetes

rats (150g), divided into four groups: control, control+ω3, diabetes and diabetes+ω3. Induction of diabetes was performed using 40mg/kg of streptozotocin iv and diabetes mellitus was diagnosed after demonstration of hyperglycaemia (glucose >11mmol/L) 7 days after the streptozotocin infusion. Animals in the control+ω3 and diabetes+ω3 groups received supplementation of 3g of ω3/ALA from flaxseed, daily for a period of 8 weeks. The ω3/ ALA was added to the diet and the animals had food and water ad libitum. Measurements of serum glucose, lipid profile serum cytokines (TNF-α, IL-6 and INF-γ) and body weight were performed before the beginning of the supplementation (T1) and by the end of this period (T2). Data of liver and epididimal fat weight were collected no T2. The diabetes+ω3 group had lower liver (p<0.001) and greater epididimal adipose tissue (p=0.04) weight in relation to the diabetes group, besides no difference in total body weight. There was no difference on the total liver lipid between the groups, as shown in Table 1. On the other hand, the control+ω3 group showed increased liver (p=0.001), epididimal (p<0.001) and body weight (p<0.001) (table). Diabetes+ω3 group showed lower glucose (p=0.01) and triglyceride (p<0.001) levels on T2 compared to

CONTROL T1

CONTROL+ω3/ALA T2

DIABETES T1

DIABETES+ω3/ALA T2

Body Weight (gr)

169.1±17.7

283.5±42.5

168.7±10.5

336±71.7 *

146.9±11.2

245.3±1.2*

158.5±11.7

225.4±0.3

Glucose (mg/dL)

153.6±17.2

100.3±9.9

141.1±8.3

92.8±6.3

471.7±54.4

517.4±67.7

482.6±35.7

431.4±58.4*

Total Cholesterol (mg/dL)

78.7±12.5

57.7±6.9*

70.1±10.4

55.4±10.0*

74.7±7.6

91±17.7*

79.2±13.6

91±14.4

Triglycerides (mg/dL)

70.7±15.7

86±22.7

68.5±21.7

114.5±30.1*&

75.8±8.8

216.8±49.7*

71.9±29.5

89.4±39.5&

Serum TNF-a (pg/mL)

40,1±21,6

21,2±12,7

32,4±12,8

18,6±18,0

13,0±7,9

30,6±5,5

29,3±28,1

30,3±13,4

Serum IL-6 (pg/mL)

105,9±38,4

81,4±25,3

116,1±36,9

95,7±23,1

44,1±28,3

37,5±17,6

74,9±31,7

50±35,3

Serum INF-g (pg/mL)

739,1±190,8

542,0±237,7

694,4±159,7

634,9±170,0

598,3±186,6

402,4±236,7

636,1±121,9

378,3±174,7*

Poster Synopsis

Treatment Strategies - Meeting Review

Table 1. Body weight and serum levels of fasting glucose, lipids and Serum cytokines level from streptozotocin induced diabetic rats (Diabetes and Diabetes+ω3/ALA) and control animals (Control and Control+ω3/ALA) supplemented or not with 3 gr/day of omega 3/ALA. Abbreviations. ω3: Ômega 3; ALA: alpha-linolenic-acid; T1: pre-treatment; T2: end of supplementation treatment; TNF-a: tumor necrosis factor-alpha; IL-6: interleucin-6; INF-g: interferon-gamma; * p<0.05 T1xT2; & p<0.05 Control or Diabetes group T2 x Control or Diabetes+ω3/ALA group T2.

Figure 1. Relative quantification of immunoblot of liver total protein extract after supplementation or not with 3 gr/day of omega 3/ALA in streptozotocin induced diabetic rats (Diabetes and Diabetes+ω3/ALA). Data are presented in relative quantification and SEM.

Diabetes group, but no difference in total cholesterol. Serum levels of TNF-α and IL6 were lower in the diabetic groups compared to the control groups but the ω3/ ALA supplementation did not determine significant changes. However, the diabetic+ω3 group showed a decrease in the INF-γ serum levels after the supplementation period, as

shown in Table 1. We also observed that diabetes+ω3 group had increased expression of BIP (p=0.002), AKT (p<0.001), HSP90 (p=0.02) and HSP70 (p=0.01). Concomitantly there was a decrease in the expression of spliced XBP1 (p<0.001), IRE1 alpha (p=0.04), DAPK1 (p=0.02) and TNF-alpha (p=0.04). There were no difference in the expression of

PERK, GADD153, unsliced XBP-1 and IL-6, as shown in Figure 1. Our data supports that daily supplementation of 3 gr of ω3/ALA was able to reduce blood glucose and triglyceride in diabetic rats associated to a reduction in systemic inflammation as observed.

Treatment Strategies - Respiratory R5 Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

Jothydev Kesavadev Chairman & Managing Director, Jothydev’s Diabetes Research Centre, Trivandrum, Kerala In the natural history of the progression of type 2 diabetes the initial hyperinsulinaemia culminates in near total decline in the beta cell function over several years. The eventual loss of beta cell function and associated insulin secretary deficiency is more rapid when HbA1c levels consistently remain high. Since the mid-1970s, C-peptide has been used as a surrogate marker for monitoring the course of type 1 and type 2 diabetes and determining the effects of interventions designed to preserve and improve residual β-cell function. In our centre, subjects registered under telemedicine based long-term follow-up care Diabetes Tele Management System (DTMS®) maintains near normal metabolic targets being followed up frequently via a multi-disciplinary trained diabetes team. DTMS® involves unique software & trained multi-disciplinary diabetes team members communicating with patients through phone/email for slow, steady titration of drugs combined with frequent telecounselling precluding physical visits to the hospital. The team consists of physicians, trained dieticians, pharmacists, nurses, diabetes educators and psychologist. Each tele-consultation offers an opportunity for education, interactive communication and trouble shooting. The frequency of education via telephone/internet is again decided based on individual requirements. The follow-up programme via the telephone or internet precludes physical visits to the

hospital and has been proven to be cost effective, as well as helping to maintain individualised HbA1c targets without significant hypoglycaemia. A cross-sectional analysis of 2076 T2DM patients aged above 20 years was performed. 37% of these patients were female. The mean age was 51.7 years SD 11.9 and C-peptide mean was 2.725 SD 1.7. A1c

Treatment Strategies - Respiratory

When compared with newly enrolled patients, patients on long-term follow-up and maintaining a low HbA1c value showed no decline in C-peptide levels while on DTMS® based care. However, newly enrolled patients with long-standing diabetes

Female

Male

Duration in Years

mean was 8.8 SD 2.1.

829 patients which had a duration of follow-up of more than 1 year and 1247 patients which had a duration of followup of less than 1 year were included in the analysis. Age and gender distribution were similar Dr. Jothydev Kesavadev is an alumnus among the two groups. of Govt. Medical College, Trivandrum Group with more than 1 and Mayo Clinic, Minnesota, USA. He has several national and international year follow up (M=8.4, SDpresentations and publications to his 1.8) had significantly lower name. His research mainly focuses on A1c compared to new cost effectiveness of telemedicine in patients with less than 1 diabetes, insulin pumps and continuous glucose monitoring. year follow-up (M=9.1%, He has been a speaker at the American Diabetes Association (ADA), International Diabetes Federation (IDF) and Advanced SD=2.2), t(2009) = 7.25, p < Technologies and Treatments for Diabetes (ATTD). He has .0001. Regression analysis also presented at the European Association for the Study of also indicated that A1c Diabetes (EASD). He dedicates his time entirely to diabetes and tends to be lower with streamlines his activities in 4 different areas: research, patient higher C-peptide (R2=0.01, care, mass education and community work. F(4,819)=2.7,p=0.02).

Linear regression also showed no significant change of C-peptide levels with duration under care, as shown in the figure below.

C- peptide

Poster Synopsis

C-peptide Levels not Affected by Duration of Diabetes in a Telemedicine Based Long-term Follow-up Programme

and higher HbA1c levels had relative low C-peptide levels. The benefits of intensive glucose lowering with proven, both shortand long-term benefits are restricted by the serious consequences of hypoglycaemia in routine diabetes care. Maintaining near normal HbA1c values by regular follow up via DTMS® based care may help preserve the beta cell function even after decades of onset of diabetes.

References

1. Luppi P, Cifarelli V, Wahren J. C-peptide and long-term complications diabetes. Pediatr Diabetes 2011;12:276–292. 2. Cost-effective Use of Tele-Medicine and Self-Monitoring of Blood Glucose via Diabetes Tele Management System (DTMS®) to Achieve Target HbA1c Values Without Serious Symptomatic Hypoglycaemia in 1000 Subjects With Type 2 Diabetes MellitusA Retrospective Study. Diabetes Technol. Ther. 2012 Sep;14(9):772–776.

Treatment Strategies - Meeting Review

50th EASD Annual Meeting Vienna, Austria,

15-19 September 2014

In 2014 the 50th anniversary of the world's leading international forum for diabetes research, the Annual meeting of the EASD will come to the Messe Wien exhibition centre, Vienna, Austria. Dedicated to diabetes and metabolism issues this conference will cover topics such as: Genetics of diabetes Prediction and prevention of diabetes Diabetes and immunology Insulin issues Lipid metabolism Diabetes in childhood Diabetes complications.

Treatment Strategies - Respiratory

www.cambridgeresearchcentre.co.uk

Treatment Strategies - Meeting Review

Statins and New Onset Diabetes: Getting to the Heart of the Matter

Introduction

countries between 1995-6 and 2006-7, and it was found that there was

The satellite symposium entitled, “Statins and New Onset Diabetes:

an overall decrease from 94.5% in 1995-6 to 46.2% in 2006-7.1 This was

Getting to the Heart of the Matter” was held during the 49th Annual

believed to be largely due to the utilisation of statins. The EUROASPIRE

Meeting of the European Association for the Study of Diabetes (EASD)

database also looked at the prevalence of diabetes over the same time

on Monday 23 September 2013 in Barcelona, Spain. The Congress was

period and found an overall increase from 17.4% to 28%. This has been

chaired by Prof. Henry N. Ginsberg, Irving Professor of Medicine and

thought to be due to an increase in the incidence of obesity, decrease

Director, Irving Institute for Clinical and Translational Research,

in physical activity and a move away from traditional to more Western

Columbia University, New York, USA.

diets in many countries.

Introduction

The metabolic syndrome associated with insulin resistance imparts a

Henry N. Ginsberg

high risk of atherogenesis, with a decrease in high density lipoprotein

(Irving Institute for Clinical and Translational Research,

(HDL) levels and an increase in triglyceride (TG) and small dense low

Columbia University, USA)

density lipoprotein (LDL) levels.2

Despite major advances in the treatment of cardiovascular disease, it remains the most common cause of death globally, and is on the increase.

The ACCORD study examined the effects of combination lipid therapy in type 2 diabetes mellitus (T2DM). They reported an annual rate for

Statins are prescribed to millions of patients diagnosed with raised

the first occurrence of non-fatal myocardial infarction, non-fatal stroke,

cholesterol levels. In the EUROASPIRE study, the prevalence of raised

or death from cardiovascular causes of 2.2% for patients treated with

total cholesterol (TC: >4.5 mmol/L) was assessed in cardiology clinics

simvastatin plus fenofibrate versus 2.4% for patients given simvastatin

among patients who had cardiac events across many European

plus placebo.3 Sub-group analysis indicated a possible interaction according to lipid subgroup, with a possible benefit for patients

Statins and New Onset Diabetes: Getting to the Heart of the Matter Kowa Pharmaceuticals Europe Sponsored Satellite Symposium at the 49th Annual Meeting of the European Association for the Study of Diabetes (EASD), Barcelona, Spain, 23rd September 2013

with both a high baseline TG level and a low baseline level of

Chair: Henry N. Ginsberg, Irving Institute for Clinical and Translational Research, Columbia University, New York, USA

The Cholesterol Treatment Trialists (CTT) meta-analysis showed

Chair’s Introduction Henry N. Ginsberg, Irving Institute for Clinical and Translational Research, Columbia University, New York, USA

regardless of whether a patient had T2DM or not.4 However, the

Pitavastatin in Cardiometabolic Disease: Therapeutic Profile Lluís Masana, Vascular Medicine and Metabolism Unit, University Hospital “Sant Joan”. Rovira and Virgili University Reus, Spain Pitavastatin and Incident T2DM Masato Odawara, Department of Diabetology, Metabolism, and Endocrinology, Tokyo Medical University, Tokyo, Japan Statin Diabetogenicity: Guidance for Clinicians Kausik K. Ray, Cardiovascular Sciences Research Centre, St. George’s University of London, UK Opportunities and Challenges in Managing Cardiometabolic Disease Henry N. Ginsberg, Irving Institute for Clinical and Translational Research, Columbia University, New York, USA

HDL-cholesterol (HDL-C) (p=0.057 for interaction).

that statin therapy reduced the risk of occlusive vascular events rates were higher if a patient had T2DM. Therefore, although the relative risk reduction was the same, the absolute risk in diabetes patients was higher. The Emerging Risk Factors Collaboration, using data from over 300,000 patients, assessed major lipids and apolipoproteins in vascular risk.5 It was shown that TG were a univariate predictor of cardiovascular disease. However, when the data were adjusted for non-lipid factors such as body mass index (BMI), age, blood pressure and smoking history, and also adjusted for HDL-C and non-HDL-C, TG were not predictors. By contrast, HDL-C and non-HDL-C (in opposite directions) were predictive of Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

food or drug-drug interactions.9

cardiovascular disease risk. The TNT study has also shown that HDL-C levels in patients receiving

The goal of statin therapy is to reduce LDL-C levels. European Society

statins are a strong inverse predictor of cardiovascular events.

of Cardiology (ESC)/ European Atherosclerosis Society (EAS) guidelines

Interestingly, when the analysis was stratified according to LDL-C

have proposed an estimation of the distance from the lipid target that

levels, the relationship remained significant.

can easily be obtained, as shown in Table 1.10 Once the distance from a

target is determined, then by interpolation from the known doseWhen it comes to the trials of statin therapy, there have been

response of statins, the best target dose for the best statin to help

conflicting findings on the risk of development of T2DM in patients

reach the lipid goal can be identiﬁed. A high-risk patient with an LDL-C

given statins. An analysis of 13 statin trials with 91,140 participants, of

value greater than 170 mg/dl requires a reduction in LDL-C levels by

whom 4,278 (2,226 assigned statins and 2,052 assigned control

more than 40%. Based on the ESC/EAS guidelines, after the withdrawal

treatment) developed diabetes during a mean of 4 years, showed that

of simvastatin 80 mg, only atorvastatin, rosuvastatin and pitavastatin

statin therapy was associated with a modest 9% increased risk for

have approved doses that can achieve mean reductions of ≥45%.

incident T2DM. The risk of developing T2DM was highest in trials with 7

older participants, but neither baseline BMI nor change in LDL-C

Other contributing factors, such as glucose, HbA1c, obesity and

concentrations accounted for the residual variation in risk. This study

glomerular filtration rate (GFR) values will impact on the LDL-C

concluded that statin therapy was associated with a slightly increased

reduction needed, and will also impact on TG and HDL-C levels.

risk of development of T2DM, but the risk was low both in absolute

Therefore, It is also important to know the impact of statins on

terms and when compared with the reduction in coronary events.

HDL-C levels.

The challenge for clinicians is to balance the need for lipid lowering versus

Pitavastatins have shown a unique HDL raising impact compared with

the risk of developing T2DM in patients with hypercholesterolaemia.

other satins.

Pitavastatin in Cardiometabolic Disease: Therapeutic Profile

In a sub-analysis of the 2-year LIVES study, pitavastatin 1 to 4 mg/day

Lluís Masana

24.6% (p<0.0001) in those with a low baseline HDL-C.11 Pitavastatin has

(University Hospital “Sant Joan”. Rovira and Virgili University

also demonstrated around a three times increase in HLD-C levels

Reus, Spain)

versus atorvastatin.12

signiﬁcantly increased HDL-C levels by 5.9% in all subjects and by

Statins differ with respect to their ring structure and substituents, and these differences affect their pharmacological properties.

It has been suggested that elevations in HDL-C and decreases in LDL-C

Pitavastatin differs from other statins in that it has a cyclopropyl

levels might slow the formation of atherosclerotic plaques and may

group on the base structure. This cyclopropyl group contributes to a

reduce the residual cardiovascular risk by increasing the rate of

more effective inhibition of the HMG-CoA reductase enzyme to

cholesterol eﬄux from cells. Of particular interest for pitavastatin were

reduce cholesterol production, and affords effective LDL-C clearance

the results from a meta-analysis of different statin studies and the

and reduction of plasma cholesterol at a lower dose.8 The difference

impact on plaque volume. It was found that, whilst the plaque volume

in structure affords pitavastatin a high degree of lipophilicity, oral

change induced by a 1% reduction in LDL-C showed little diﬀerence

absorption and bioavailability, which negates concerns regarding

using a number of diﬀerent statins (atorvastatin, pravastatin,

Starting LDL-C

% Reduction to reach LDL-C

mmol/L

~mg/dL

>6.2

>240

<1.8 mmol/L

<2.5 mmol/

<3 mmol/L

(~70 mg/dL)

(~100 mg/dL)

(~115 mg/dL)

>70

>60

>55

5.2–6.2

200–240

65–70

50–60

40–55

4.4–5.2

170–200

60–65

40–50

30–45

3.9–4.4

150–170

55–60

35–40

25–30

3.4–3.9

130–150

45–55

25–35

10–25

2.9–3.4

110–130

35–45

10–25

<10

2.3–2.9

90–110

22–35

<10

1.8–2.3

70–90

<22

Table 1. Percentage reduction of LDL-C requested to achieve goals as a function of the starting value.

Treatment Strategies - Diabetes

Treatment Strategies - Meeting Review

pitavastatin, rosuvastatin, simvastatin), pitavastatin delivered the

world, and Japan is no exception.24, 25 It is known that statins reduce the

greatest reduction in plaque volume per 1% increase in HDL-C.13

risk of cardiovascular disease in Western countries. To see if the same was true for the Japanese community, the MEGA study examined the

There has been some concern raised regarding the impact of statin use

impact of diet plus pravastatin versus diet alone on lipid levels in a

on the development of diabetes. A recent study has shown that

group of this population with hypercholesterolaemia.26 The study

pitavastatin 4 mg has no effect on glycaemic parameters in metabolic

demonstrated a 33% (p=0.01) decrease in cardiovascular risk with the

syndrome at 6 months. In addition, HbA1c levels were shown to

introduction of statin therapy. Sub-analysis found that statin therapy

decrease after 104 weeks of treatment with pitavastatin in people with

was also equally or more effective in diabetic patients with

diabetes in the LIVES study.

hypercholesterolaemia. However, there is a concern regarding the

potential for some statins to induce T2DM. In the Jupiter trial, Diabetic patients treated with statins frequently require polypharmacy.

rosuvastatin therapy was associated with an increased incidence of

Therefore, drug-drug interactions are also a key concern. Most statins are

new onset T2DM versus placebo.27 In contrast to this, a sub-analysis of

metabolised through cytochrome p450, isoform 3A4. As around 30% of

the WOSCOP data found that treatment with pravastatin reduced the

these patients are on 3A4 inhibitors at the same time, this has the potential

incidence of T2DM by 30% versus placebo. However, this study used a

for drug-drug interactions. The unique structure of pitavastatin reduces

non-classical definition of T2DM, including an increase of 36 mg/dL in

the potential for these drug-drug interactions.16 Pitavastatin’s cyclopropyl

fasting blood glucose as a criterion, due to study data limitations.

group diverts the drug away from metabolism by CYP3A4 and allows only a small amount of clinically insigniﬁcant metabolism by CYP2C9.

In order to establish if any relationship existed between statin use and development of diabetes, a meta-analysis of several statin trials was

As with all drugs, it is important to be aware for the potential of

carried out.7 The study found that, across 13 trials for atorvastatin,

adverse events (AEs). Only 10.4% of pitavastatin-treated patients

simvastatin, rosuvastatin, pravastatin and rosuvastatin, statin therapy

experienced adverse events (AEs), of which approximately 84% were

was associated with a modest 9% increased risk for incident diabetes

mild and around 1% was severe. Increases in blood creatine

with little heterogeneity between trials. Meta-regression showed that

phosphokinase (2.7%), alanine aminotransferase (1.8%), myalgia

the risk of developing diabetes with statins was highest in trials with

(1.1%), aspartate aminotransferase (1.5%) and gamma-

older participants, but neither baseline BMI nor change in LDL-C

glutamyltransferase (1.0%) were the most common AEs. Only 7.4% of

concentrations accounted for the residual variation in risk.

patients discontinued pitavastatin due to AEs. In Japan, J-PREDICT is a recently completed open-label, randomised, Three out of four patients on pitavastatin achieve LDL targets,

controlled, parallel-group comparative study to evaluate the effect of

including the elderly population.18-20 Pitavastatin has also shown

pitavastatin versus lifestyle modiﬁcation on the risk of diabetes in a

beneficial effects on GFR and albuminuria.

target population of 1,240 subjects with impaired glucose tolerance over

11, 21, 22

5 years.28 This is the first study evaluating the incidence of diabetes as a In the CIRCLE study, which compared the efficacy of different statins on

primary outcome in a prospective manner. Early results show that the

serum lipid levels and the association between those changes and

cumulative incidence rate of T2DM as defined in the primary endpoint

cardiac events in patients after percutaneous coronary intervention,

was significantly reduced (p=0.041) by 18% with pitavastatin (HR 0.82

each statin significantly prevented major adverse cardiac events

(95% CI: 0.68-0.99)) versus lifestyle modification alone.29

(MACE) compared with no statin. However, pitavastatin was found to 23

be the most effective.

Statin Diabetogenicity: Guidance for Clinicians Kausik K. Ray

Based on the available data for pitavastatin, it can be seen that a

(St. George’s University of London, UK)

wide range of patients are suitable for therapy. These include

It is important to establish whether or not hyperglycaemia has a

patients with the need for 40% or higher reductions in LDL-C levels;

negative impact on cardiovascular risk. In people who develop T2DM

those who have acute coronary syndrome with coronary lesions;

over the age of 40 years, the average number of years of life lost is

those with low HDL-C levels; those on more than one medication;

around 6-7, mostly from vascular disease.30 If T2DM develops later in

the elderly; and patients who are either diabetic, pre-diabetic or

life, it has less of an impact. In another study, that included 528,877

have chronic kidney disease.

participants, T2DM was found to double the risk of vascular disease after adjusting for age, sex, cohort, systolic blood pressure, smoking

Pitavastatin and Incident T2DM

and BMI.31 However, cardiovascular disease risk from diabetes is not

Masato Odawara

explained by conventional risk factors. Dysglycaemia (below 7mmol/L)

(Tokyo Medical University, Japan)

is a modest cardiovascular risk factor,31 and early onset T2DM is

The incidence of T2DM and pre-diabetes is on the increase across the

equivalent to previous MI and no diabetes in terms of cardiovascular Treatment Strategies - Diabetes

risk.32 A meta-analysis of randomised controlled trials has shown that,

As we have seen earlier, statins can increase the risk of dysglycaemia,

although intensive compared with standard glycaemic control

and this risk increases with increasing age.7 However, a recent

significantly reduces coronary events without an increased risk of

meta-analysis of statin trials has shown that, although intensive statin

death, a greater benefit was achieved by 4 mmHg systolic blood

therapy is associated with a higher incidence of new-onset T2DM, it is

pressure lowering (-12.5% cardiovascular events) and by a 1 mmol/L

also associated with fewer major cardiovascular events. In absolute

lower LDL-C reduction (-8.2%), compared with a 0.9% lower HbA1c

terms this analysis found that there was 1 additional case of T2DM for

(-2.9%). Another study has shown that although the oral

every 498 patients treated for 1 year compared with 1 fewer patient

hypoglycaemic, rosiglitazone, substantially reduces incident T2DM,

experiencing a cardiovascular event for every 155 patients treated for 1

there appeared to be little or no effect on cardiovascular events.

year. This would suggest that there is a net cardiovascular benefit in

high-risk individuals strongly favouring statin therapy. However, the When it comes to lipid lowering, the CTT analysis showed that a

long-term consequences are unclear, particularly with regard to

reduction in LDL-C, regardless of the initial lipid profile or other

microvascular disease.

presenting characteristics, is associated with a clear reduction in a 21% reduction in any major vascular event (p<0.0001). A follow-up CTT

Opportunities and Challenges in Managing Cardiometabolic Disease

analysis found that statin therapy reduced cardiovascular event risk

Henry N. Ginsberg

cardiovascular events.35 In fact, per mmol/L reduction in LDL-C, there was

irrespective of diabetes status. In a more recent CTT meta-analysis of

(Irving Institute for Clinical and Translational Research, Columbia

data from 170,000 participants in 26 randomised trials, more intensive

University, USA)

lowering of LDL-C resulted in definite further reductions in the incidence

Cardiovascular disease and T2DM are a growing burden on healthcare

of heart attack, of revascularisation, and of ischaemic stroke, with each

systems. In the management of patients with cardiometabolic disease,

1.0 mmol/L reduction, resulting in a decrease in the annual rate of these

statins are used with the understanding that a slightly increased risk of

major vascular events by just over a fifth.36

diabetes is outweighed by the cardiovascular benefits of the drugs.

Although meta-analyses of the major clinical trials indicate that Regarding the safety of statins, there is no evidence of an overall

statin-associated risk of developing diabetes is a class effect, further

increased risk of cancer or at any particular site. In the PROVE-IT study,

studies are needed to determine whether all statins carry the same risk

no significant differences in safety parameters in the very low LDL

of increasing incident diabetes. For the present, physicians should

groups were reported, including muscle, liver, or retinal abnormalities,

continue to use statins with confidence, but should monitor for the

intracranial haemorrhage, or death.38

development of diabetes, especially in high-risk patients.

References 1. Kotseva K. Lancet 2009;373:929-40. 2. Nesto RA. Am J Cardiovasc Drugs 2005;5:379-87. 3. ACCORD Study Group. NEJM 2010;362;1563-74. 4. CTT. Lancet 2008;371:117-25. 5. Emerging Risk Factors Collaboration. JAMA 2009;302:1993-2000. 6. Barter P et al. NEJM 2007;357:1301-10. 7. Sattar N et al. Lancet 2010,375:735-42. 8. Morikawa. J Atheroscler Thromb 2000;7:138-44. 9. Mukhtar RYL et al. Intl J Clin Pract 2005;59:239-52. 10. European Society of Cardiology (ESC)/ European Atherosclerosis Society (EAS) guidelines. Eur Heart J doi:10.1093/eurheartj/ehr169. 11. Teramoto T et al. Expert Opin Pharmacother 2010 11:817-82. 12. Sasaki J et al. Clin Ther 2008;30:1089-101.

Treatment Strategies - Diabetes

13. Kishida K et al. Cardiovasc Hematol Disord Drug Targets 2012;12:28-34. 14. Hounslow N et al. In press. 15. Ming EE et al. Clin Lipidol 2008;2:453-63. 16. Hirano M et al. J Pharmacol Exp Ther 2004;311:139-146. 17. Teramoto T et al. Jpn Pharmacol Ther 2011; 39: 789-803. 18. Ose L et al. Curr Med Res Opin 2009;25:2755-64 19. Stender S et al. Atherosclerosis Supplements 2009;10:P770. 20. Graham I et al. Atherosclerosis 2007;194:1-45. 21. Kimura K et al. J Ath Throm 2010;17:601-9. 22. Nakamura T et al. Pharmacol Res 2010;61:58-61. 23. Maruyama T et al. Circ J 2011;75:1951-9. 24. Diabetic investigation of MHLW 1999 and 2002.

25. The National Health and Nutrition Survey in Japan, 2006 and 2007. 26. Nakamura H et al. Lancet 2006;36:1155-63. 27. Ridker PM et al. N Engl J Med 2008;359:2195-207. 28. Yamazaki T et al. Diabetol Int 2011;2:134-40. 29. Odawara M et al. Diabetes 2013;62 (Suppl 1A): LB17. 30. Seshasai SR et al. N Engl J Med 2011;364:829-41. 31. Seshasai SR et al. Lancet 2010;375:2215-22. 32. Wannamethee SG et al. Arch Intern Med 2011;171:404-10. 33. Ray KK et al. Lancet 2009;373:765-72. 34. Gerstein HC et al. Lancet 2006;368:1096-1105. 35. CTT Collaborators. Lancet. 2005;366:1267-78. 36. CTT Collaborators. Lancet 2010;376:1670-81. 37. Baigent C et al. Lancet 2005;366:1267-78. 38. Wiviott SD et al. J Am Coll Cardiol 2005;46:1411-6.

Treatment Strategies - Diabetes and Cardiovascular Risk

Obstructive Sleep Apnoea, Type 2 Diabetes and Cardiovascular Consequences Henri Tuomilehto1, 2 1. Oivauni Sleep Clinic, Kuopio; 2. Institute of Public Health and Clinical Nutrition, University of Eastern Finland

Introduction

men, 3% among 30-49 year-old women and 9% among 50-70

Sleep disorders have become a public health concern in modern

year-old women.6 Since excessive daytime sleepiness is the main

society, affecting millions of people. Besides causing subjective

reason for patients seeking medical help, this suggests that a great

discomfort, such as excessive daytime sleepiness, sleep disorders have

number of patients (up to 80-90%) remain undiagnosed.7

been associated with an increased morbidity and mortality.

Obstructive sleep apnoea (OSA) is one of the most common sleep

Pathophysiology and Risk Factors for OSA

disorders, and has become a major burden on our healthcare system

The pathophysiology of OSA is complex and most likely multifactorial,

over the last few years. OSA mostly affects the middle-aged work force,

consisting of a combination of predisposing anatomical factors and

causing a major negative impact on public health.2 Furthermore, OSA

impaired neuromuscular compensatory responses.8 However, obesity is

has also been found to be tightly linked with metabolic abnormalities,

considered to be the most important risk factor for OSA, and a BMI >

particularly Type 2 diabetes (T2D), and cardiovascular morbidity.3

29 increases the risk for OSA 10-fold. It has been estimated that 60–90% of all patients with OSA are obese.9 Weight gain increases the

Symptoms and Epidemiology of OSA

possibility for the development of OSA in previously healthy people,

The recurrent upper airway obstruction and the resulting

and accelerates the progression of earlier diagnosed OSA, particularly

interruptions in breathing during sleep characterised by OSA are

in patients who are already overweight.10, 11 The other major

manifested as loud snoring, pauses in breathing, and sleep

predisposing factors for OSA are male gender, age and certain

fragmentation. Due to the sleep fragmentation, OSA is often

anatomical factors e.g. large tonsils, prominent uvula, mandibular

accompanied by daytime symptoms; fatigue, lack of concentration,

micrognathia and nasal deformities.12 Due to all these factors, the

irritation, morning headache, impotence, deterioration of an

airspace of the naso- and oropharynx decreases and there is a

individual’s quality of life and working capacity.

narrowing of the upper airways, thus increasing the risk of OSA in the

4, 5

However,

symptoms and knowledge about OS may vary greatly between

supine position and a loss of neuromuscular compensation at the

individuals. Furthermore, humans tend to adjust to their situation

onset of sleep.

despite it being less than ideal. Thus, a majority of OSA patients live their everyday life without knowing that they actual suffer from a

OSA and T2D

serious disease. The prevalence of OSA has increased significantly

In clinical work, the association between T2D and OSA should be

over the last two decades. Recent estimates of moderate to severe

firmly kept in mind. Patients with OSA are found to have an increased

OSA are 10% among 30-49 year-old men, 17% among 50-70 year-old

risk for T2D (approx. 40% of people with OSA will have T2D), but the incidence of new T2D or different stages of hyperglycaemia in people

Henri Tuomilehto was appointed as Adjunct Professor in 2009 at University of Kuopio, Finland. He is currently the Head Physician of Oivauni Sleep Clinic, Kuopio and Tampere, Finland. Dr. Tuomilehto founded the Kuopio Sleep Apnoea group in 2004 when starting the first randomised study evaluating the effects of lifestyle intervention in patients with obstructive sleep apnoea (OSA). It is one of the landmark studies examining the effects of weight loss in OSA. Currently, his main research project is “Early Prevention of Diabetes Complications in Europe”: a multi-centre study on obesity, metabolism and obstructive sleep apnoea.

with OSA is not known.3, 13 The severity of OSA also seems to be linked with worsened insulin resistance and glucose control in diabetes.14 On the other hand, it has been demonstrated that patients with T2D may have a very high prevalence (60-85%) of OSA.3, 13 Both conditions are chronic diseases that progress from mild sleep disordered breathing or hyperglycaemia to more severe condition over a varying period of time, which may be surprisingly short in the case of weight gain and lack of effective treatment. The studies examining these associations have unfortunately, thus far, consisted Treatment Strategies - Diabetes

Treatment Strategies - Diabetes and Cardiovascular Risk

of only small sample sizes (n=60-200).3, 13 The main proposed

the exact underlying mechanisms leading to these associations are

mechanisms causing the association include hypoxaemia and sleep

still not fully understood, but it is most likely that they are

fragmentation, which may alter glucose and insulin metabolism by

multifactorial and highly influenced by the common feature of

elevating chronic inflammation and sympathetic activity. However,

obesity, and in particular central obesity.3, 13, 14 Thus, there exists a

Obstructive sleep apnoea Sleep fragmentation Intermittent hypoxemia • Sympathetic activity  • Oxidative stress  • Low-grade inflammation • Dyslipidemia

ys wa air ion r pe irat up of f resp n tio t o uc en str airm b O p Im

An i

nd e ad pen dit de ive nt ris and kf ac pos to sib r le

Cardiovascular complications

Obesity Hyperglyceamia Low-grade inflammation  Oxidative stress Endothelial dysfunction Hypercholesterolemia

Micro- and macrovascular Ischemic heart diseases Arrhythmias Hypertension Retinopathy, nephropathy

The traditional pathway

Figure 1. The major mechanisms for cardiovascular complications in obese patients. In hyperglycaemic patients with OSA both A (traditional) and B (related to OSA) pathways are activated.

Change in OSA

Change in AHI 1

4 .8 2

Proportion with OSA at 12 month, n= 72

Change in AHI from baseline to 12 month, n= 72

0 -2 -4 -6 -8 -10 -12

-14 -16 0

-18 <-15 kg

-15 to -5 kg

-5 to 0 kg

>0 kg

Weight change at 12 months follow-up

<-15 kg

-15 to -5 kg

-5 to 0 kg

>0 kg

Weight change at 12 months follow-up

Figure 2. Changes in apnoea-hypopnoea index (AHI) in relation to changes in body weight, and the proportion of patients (%) with OSA (AHI>5) in relation to the weight change categories <-15 kg, -15 to -5kg, -5kg to 0kg, and >0kg at the 12-month follow-up. Reprinted with permission of the American Thoracic Society. Copyright © American Thoracic Society. Tuomilehto H et al. Am J Respir Crit Care Med 2009;179:320-7. Official Journal of the American Thoracic Society. 56

Treatment Strategies - Diabetes

Treatment Strategies - Diabetes and Cardiovascular Risk

need to improve our knowledge on the association between

Furthermore, little is known about the associations between different

cardiometabolic syndrome and OSA, and the effect of weight loss in

stages of OSA and hyperglycaemia, particularly in the early phases of

all co-morbidities related to obesity.

the diseases. Also, reliable scientific evidence on the effect of treating these conditions with healthy diet and increased physical activity,

OSA, T2D and Cardiovascular Consequences

and the effect that this has on the development of cardiovascular

A linear relationship exists between hyperglycaemia and

complications is lacking. Often these conditions are present in the

microvascular complications. For instance, impaired glucose

same individual, and it has been suggested that the co-existence of

tolerance is associated with a 40% of increased mortality and the risk

OSA, obesity, insulin resistance, hypertension and dyslipidaemia may

of both microvascular and macrovascular complications. T2D leads

have a more widespread impact on the cardiovascular complications

to both macro- and microvascular complications that are responsible

than these conditions could on their own20 (Figure 1). The consensus

for most of the associated excess morbidity and mortality. While

statement of International Diabetes Federation (IDF) urges action to

macrovascular complications such as cardiovascular disease are the

raise awareness and recommends that all healthcare professionals

most frequent cause of excess mortality, microvascular complications

involved with T2D or OSA should be educated about the links

such as retinopathy and nephropathy are responsible for much of the

between the two conditions and trained in their care. Further

excess morbidity. OSA is also an important risk factor for increased

research is needed to better understand the links between the two

mortality. This is particularly due to coronary artery disease and even

conditions and improve treatment and care.21

mild OSA is associated with increased activation of the inflammatory system and a risk for cardiovascular morbidity, although the risk is

Treatment for OSA

more frequently associated with more severe degrees of the

The gold standard for treating patients with OSA is nasal continuous

disease.17, 18 Our study group has demonstrated that sleep

airway pressure (CPAP). It has been found to be effective for removing

disturbances may predict a progression from pre-diabetes stages to

the abnormal respiratory events, as well as reducing the cardiovascular

T2D.19 However, it is still unclear whether sleep disorders, such as

morbidity and mortality related to OSA.18, 22 Therefore, CPAP is a first-line

OSA, further increase the risk for micro- (i.a. endothelial dysfunction,

treatment for patients with more severe OSA and/or when the disease is

retinopathy, nephropathy) or macrovascular complications in people

accompanied with significant impairment in daytime performance.

with hyperglycaemia. If so, and considering the suggested high

However, adherence (60-80%) to the treatment may sometimes be a

prevalence of OSA linked to T2D, it would be essential to find the risk

major limitation, particularly in early, mild-moderate symptomatic stages

group and properly treat OSA in people with hyperglycaemia.

of the disease (the largest subgroup approx. 70-80% of all OSA patients). Moreover, there is little evidence about

Progression of OSA by treatment

the possible beneficial metabolic

0.50

Cumulative incidence

0.40

effects of CPAP.20 One must keep in mind that obesity is the most important risk factor for

Number of events: Control: 14, Intervention: 6 Incidence rates: Control: 0.7 (95% CI 0.4-1.3), Intervention: 0.3 (95% CI 0.1-0.7) Log-rank test: p=0.043 Hazard ratio=0.387 (95% CI 0.150-0.998), p=0.049

both OSA and T2D, and in fact most OSA patients (> 70%) and diabetics

0.30

are obese.3, 9 In the first randomised study on the topic, our study group

0.20

has recently demonstrated that lifestyle intervention can be a curative treatment in moderately obese

0.10

patients with mild OSA23 (Figure 2). Later, this finding has been supported by two other RCTs; one on diabetic

0.00 0 3

Follow-up time, months Control

Intervention

Figure 3. Progression of OSA by treatment group during the post-intervention follow-up period. KaplanMeier estimate of probability of progression of OSA. The difference between the survival curves was tested with the log-rank test. The COX proportional hazard model was used to estimate the hazard ratio for the progression of OSA. Reprinted with permission of the JAMA Internal Medicine. Copyright ÂŠ American Medical Association. Tuomilehto H et al. JAMA Intern Med 2013, Apr 15.

patients and another on patients with moderate-severe OSA with CPAP treatment.24, 25 It has been reported that it is more difficult to improve OSA by weight reduction than to develop or further deteriorate OSA by more weight gain.10 This finding clearly highlights the importance of Treatment Strategies - Diabetes

Treatment Strategies - Diabetes and Cardiovascular Risk

maintaining a normal body weight by providing general information to

demonstrated, in the first study, long-term evidence that a healthy

the public via prevention programmes, or in the case of individuals

lifestyle i.e. changes in diet according to the current recommendations

who are overweight, committing them to early control of their

and increased physical activity along with weight reduction, can result

condition and more active treatment. However, regardless of promising

in marked improvements of OSA in overweight patients that are

results in terms of symptoms of OSA and the undoubted

sustained even four years after the cessation of the active intervention,

cardiometabolic benefits of changing lifestyles, weight reduction as a

and the progression of the disease prevented30 (Figure 3).

treatment of OSA is still fiercely underrated.

Based on the statement of IDF, weight reduction should be the primary OSA is a chronic, progressive disease, and it is well-documented that

treatment strategy, and the primary aim of research should be the

severe OSA is associated with an increased risk for cardiovascular

implementation of interventional studies that analyse the effects of

morbidity and mortality. Furthermore, the vast majority of people with

various therapies for OSA in people with T2D, particularly focusing on

OSA still remain undiagnosed. Intervention through lifestyle changes

cardiovascular outcomes, and the mechanism linking OSA with T2D.16

has already been successfully used in the prevention of Type 2

Thus, there is a definite need for larger, well-controlled trials on the effects

diabetes,27, 28 and also in larger scale in the implementation

of different lifestyle programmes among OSA patients to determine the

programmes for the prevention of Type 2 diabetes in clinical settings.

overall efficacy of different treatment modalities and their long-term

There are no national programmes for screening OSA or preventing the

succession before larger scale programmes may be implemented in

progression of the disease, as there are for T2D. Just recently we

clinical settings, as has been the case for the prevention of T2D.

References 1. Punjabi NM, Caffo BS, Goodwin JL, et al. Sleepdisordered breathing and mortality: a prospective cohort study. PLoS Med. 2009;6:e1000132. 2. Skaer TL, Sclar DA. Economic implications of sleep disorders. Pharmacoeconomics. 2010;28:1015-23. 3. Tasali E, Mokhlesi B, Van Cauter E. Obstructive sleep apnea and type 2 diabetes: interacting epidemics. Chest. 2008;133:496-506. 4. Hiestand DM, Britz P, Goldman M, et al. Prevalence of symptoms and risk of sleep apnoea in the US population. Result from the National Sleep Foundation Sleep in America 2005 Poll. Chest 2006;130:780-786. 5. Finn L, Young TB, Palta M, et al. Sleep-disordered breathing and self-reported general health status in the Wisconsin Sleep Cohort Study. Sleep 1998;21:701-706. 6. Peppard PE, Young T, Barnet JH, et al. Increased Prevalence of Sleep-Disordered Breathing in Adults. Am J Epidemiol. 2013 Apr 14. [Epub ahead of print] 7. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnoea. A population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239. 8. Schwartz AR, Patil SP, Squier S, et al. Obesity and upper airway control during sleep. J Appl Physiol. 2010;108:430-5. 9. Pillar G, Shehadeh N. Abdominal fat and sleep apnoea: the chicken or the egg? Diabetes Care 2008;31:303-9. 10. Newman AB, Foster G, Givelber R, et al. Progression and regression of sleep-disorders breathing with changes in weight. Arch Intern Med 2005;165:2408-2413 11. Berger G, Berger R, Oksenberg A. Progression of snoring and obstructive sleep apnoea: the role of increasing weight and time. Eur Respir J. 2009;33:338-45. 12. Young T, Skatrud J, Peppard PE. Risk factors for obstructive sleep apnea in adults. JAMA 2004;291:2013-2016. 13. Pamidi S, Aronsohn RS, Tasali E. Obstructive sleep

Treatment Strategies - Diabetes

apnea: role in the risk and severity of diabetes. Best Pract Res Clin Endocrinol Metab. 2010;24:703-15. 14. Aronsohn RS, Whitmore H, Van Cauter E, et al. Impact of untreated obstructive sleep apnea on glucose control in type 2 diabetes. Am J Respir Crit Care Med. 2010 Mar 1;181(5):507-13. 15. Balkau B, Hu G, Qiao Q, et al; DECODE Study Group; European Diabetes Epidemiology Group. Prediction of the risk of cardiovascular mortality using a score that includes glucose as a risk factor. The DECODE Study. Diabetologia 2004;47:2118-28. 16. Diabetes Prevention Program Research Group. The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med 2007; 24:137–144. 17. Sahlman J, Peltonen M, Miettinen K, et al. Activation of inflammatory cytokine system in mild obstructive sleep apnoea. J Sleep Res. 2010;19:341-348. 18. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-1053. 19. Tuomilehto H, Peltonen M, Partinen M, et al. Sleep duration, lifestyle intervention, and incidence of type 2 diabetes in impaired glucose tolerance: The Finnish Diabetes Prevention Study. Diabetes Care. 2009 Nov;32(11):1965-71. 20. Lévy P, Bonsignore MR, Eckel J. Sleep, sleepdisordered breathing and metabolic consequences. Eur Respir J. 2009;34:243-60. 21. Shaw JE, Punjabi NM, Wilding JP, et al. International Diabetes Federation Taskforce on Epidemiology and Prevention. Sleep-disordered breathing and type 2 diabetes. Diabetes Res Clin Pract. 2008;81:2-12. 22. Marin JM, Agusti A, Villar I, et al. Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012 May 23;307(20):2169-76. 23. Tuomilehto H, Seppä J, Partinen M, et al. Lifestyle

Intervention with Weight Reduction-First Line Treatment in Mild Obstructive Sleep Apnea. Am J Respir Crit Care Med 2009;179:320-7. 24. Foster GD, Borradaile KE, Sanders MH, et al.; Sleep AHEAD Research Group of Look AHEAD Research Group. A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD study. Arch Intern Med. 2009;169:1619-26. 25. Johansson K, Hemmingsson E, Harlid R, et al. Longer term effects of very low energy diet on obstructive sleep apnoea in cohort derived from randomised controlled trial: prospective observational follow-up study. BMJ. 2011 Jun 1;342:d3017. doi: 10.1136/bmj.d3017. 26. Tuomilehto H, Seppä J, Uusitupa M. Obesity and obstructive sleep apnea – clinical significance of weight loss. Sleep Med Rev. 2012 Oct 15. [Epub ahead of print] 27. Knowler WC, Fowler SE, Hamman RF, et al. Diabetes Prevention Program Research Group. 10-year followup of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677-86. 28. Lindström J, Ilanne-Parikka P, Peltonen M, et al. Finnish Diabetes Prevention Study Group. Sustained reduction in the incidence of type 2 diabetes by lifestyle intervention: follow-up of the Finnish Diabetes Prevention Study. Lancet. 2006;368:1673-9. 29. Saaristo T, Moilanen L, Korpi-Hyövälti E, et al. Lifestyle intervention for prevention of type 2 diabetes in primary health care: one-year follow-up of the Finnish national diabetes prevention program (FIN-D2D). Diabetes Care. 2010;33:2146-2151. 30. Tuomilehto H, Seppä J, Uusitupa M, et al.; for the Kuopio Sleep Apnea Group. Weight reduction and Increased Physical Activity to Prevent the Progression of Obstructive Sleep Apnea: A 4-Year Observational Postintervention Follow-up of a Randomized Clinical Trial. JAMA Intern Med. 2013 Apr 15:1-2. doi: 10.1001/ jamainternmed.2013.389. [Epub ahead of print]

Treatment Strategies - Glucose Monitoring

Continuous Glucose Monitoring: Why it is Not Enough and What Can We Expect of the Closed Loop? Martin Prázný 3rd Department of Internal Medicine, Diabetes Centre,1st Faculty of Medicine and General Faculty Hospital, Prague

Introduction

industry to diabetology since the first clinical use of insulin in 1922.

Continuous glucose monitoring (CGM) is one of the most discussed technological advantages in diabetology in recent years. It can be

Type 1 Diabetes and SMBG

compared to the start of the era of personal blood glucose meters in

It has repeatedly been shown that self-monitoring of blood glucose

the 1980s, the difference being that CGM provides glucose monitoring

(SMBG) with personal blood glucose meters significantly improves the

at a higher qualitative level. Continuous glucose monitoring brings

metabolic control of diabetes in Type 1 diabetic patients. The degree of

new therapeutical and educational possibilities for both patients and

improvement is related to the frequency of SMBG.1 Frequent

physicians. The continuous aspect of glucose measurement provides a

measurement of blood glucose facilitates precise insulin dosing and is

complex insight into the glucose metabolism in patients with diabetes

a prediction of blood glucose levels. However, this requires a lot of

and enables them to connect common daily activities with glucose

concentration on the glucose trends and keeping in mind not only the

excursions, which was previously often incomprehensible and

last measured value but rather a whole series. For some patients,

problematic. This gives patients a chance to avoid certain activities in

especially for those with high glycaemic variability, it is extremely

order to prevent undesirable blood glucose changes and/or to adjust

difficult to connect these series of results into a continuous line and

their lifestyle to minimise its impact on blood glucose levels. CGM also

predict the future development of glycaemia. For these patients, many

helps patients to reach their target glucose range without increasing

of their blood glucose values are difficult to comprehend, and this lack

the risk of hypoglycaemia during self-management and facilitates the

of understanding prevents them from administoring the precise insulin

delivery of better support to the patients from healthcare

dosing. Imprecisions in insulin substitution then often lead to

professionals. New possibilities have arisen based on the recent

hyperglycaemia and, more importantly, to hypoglycaemia.

advantages in the development of the closed-loop systems for insulin delivery. Currently, patients with diabetes still need to put a lot of

Hypoglycaemia and the Fear of it

energy into monitoring blood glucose, calculating carbohydrates,

Hypoglycaemia is currently the main obstacle in reaching the target

precisely dosing insulin and balancing their physical activity with all of

glucose range safely with insulin2 and is also a significant direct cause

the aforementioned factors. Closed-loop systems have the potential to

of mortality in patients with diabetes. Some authors estimate that

rid them of this burden and return the lost spontaneity to their lives.

about 6-10% of overall mortality of patients with Type 1 diabetes are

This may be, in fact, one of the most significant contributions of the

related to hypoglycaemia,3 a high number for an iatrogenic complication. Fear of hypoglycaemia is often present in patients with

Martin Prázný is an Associate Professor of Internal Medicine at 1st Faculty of Medicine, Charles University in Prague. He works in a diabetes research group at 3rd Department of Internal Medicine, traditionally aimed at endocrine and metabolic diseases. During his PhD studies, he published several original papers in the field of microvasculature, endothelial function and oxidative stress in patients with diabetes and other endocrine disorders. For many years, he has utilised the advances of technologies in diabetes. Recently, his research group has become more involved in clinical research in Type 1 diabetes. With better availability and reliability of continuous glucose monitoring, he investigates the role of glycaemic variability in glycaemic control and diabetes complications. He has also launched a series of postgraduate education courses on CGM use in the Czech Republic to bring this technology to healthcare professionals and to patients.

recurrent severe hypoglycaemia and may negatively impair their quality of life. Unsatisfactory diabetes control due to fear of hypoglycaemia, on the other hand, seems to be a more significant problem in patients on multiple daily injections (MDI) than in those treated with insulin pumps (CSII).4 Sensor-augmented insulin pump (SAP) treatment improves the fear of hypoglycaemia significantly,5, 6 while the benefit on HbA1C is preserved. It was shown in several studies that CGM reduces the total time spent in hypoglycaemia,7, 8 however, the effect of CGM or SAP on the frequency of hypoglycaemic episodes is still unclear. This may imply that even if CGM or SAP would not prevent hypoglycaemic episodes, it can significantly reduce their Treatment Strategies - Diabetes

Treatment Strategies - Glucose Monitoring

Lunch

Breakfast

Dinner

20.0 Glucose (mmol/L) 15.0

10.0 7.8 3.9 2.2

Figure 1. CGM record of well controlled patient with Type 1 diabetes.

duration. This may be very important in the prevention of

makes small adjustments to the recommended dose – the dose

hypoglycaemia-induced seizures. In addition, it was shown that SAP

suggested by the calculator is decreased by the patient by

also reduces glycaemic variability in patients with Type 1 diabetes with

approximately 0.8 U/day and increased by 1.3 U/day ). To cover

HbA1C less than 8% (DCCT) in the STAR 3 study.

carbohydrate intake, this patient needs 7.2 U/day and 2.8 U/day is

injected to correct glycaemia to the target range. Her postprandial

Precise Insulin Dosing with CGM

glucose control after dinner can be seen in Figure 2. Mean dose of

Precise insulin dosing, a low count of hypoglycaemic events and

insulin before dinner is 3.4 U. Mean blood glucose before dinner is 6.3

excellent glycaemic control are the targets of diabetes treatment for all

mmol/L and after dinner 7.2 mmol/L – the postprandial glucose peak is

patients. However, only a minor percentage of patients achieve this.

thus less than 1 mmol/L. The overall frequency of self-reported

Most patients perform SMBG up to 4-6 times per day, and even the

hypoglycaemia is low, and minor hypoglycaemia occurs usually 2 times

most dedicated rarely use it more frequently. For patients with Type 1

in a week. This is well-recognised by the patient. No severe

diabetes, frequency of SMBG may also predict the probability of

hypoglycaemia was reported in the last three years. The HbA1C of this

long-term CGM benefit.11 An example of a well-controlled patient is

patient is 49 mmol/M (IFCC), which is equivalent to 6.6% (DCCT).

given below. Her CGM record is shown in Figure 1.

Efficacy of Sensor-augmented Pump Therapy This patient is 62 years old and has had diabetes for 28 years. Her main

In accordance with this case report, it has recently been concluded in a

motivation for keeping tight glycaemic control is proliferative

meta-analysis that CGM may improve diabetes control in patients with

retinopathy and preventing it from worsening. She uses a sensor-

Type 1 diabetes, especially in insulin pump users.12, 13 In patients using

augmented insulin pump. In addition, she is performing SMBG with an

SAP, a significant improvement in glucose control was persistent for 3

average frequency of 6.4 times per day. The mean sensor glucose is

years.5 The efficacy of the SAP is dependent of the time spent on the

6.6±2.1 mmol/L, total mean insulin dose 24.9±3.7 U/day and 63% of

glucose sensor7 and is based on a combination of advantages of both

the total dose is given in boluses. The total daily count of boluses is 9 at

sensor and the pump. The pump enables precision tuning of the insulin

average, and the bolus calculator is used 4 times/day (patient usually

therapy for very insulin-sensitive patients. This is sometimes not possible with insulin pens which, at best, give insulin in half-unit steps. Continuous glucose monitoring not only shows patients their current

20.0

glucose levels but also warns them when they reach their high and low glycaemic threshold. Moreover, CGM devices or sensor augmented pumps calculate the rate of change in glucose concentration and show

15.0

glycaemic trends. These systems can give a warning to the patient when the rate of glucose rises or the fall is too swift. The predictive alarms are triggered in advance so that patients have some time left to react; to

10.0

adjust the insulin dose, carbohydrate intake and/or physical activity to prevent hyperglycaemia or hypoglycaemia.

7.8

Patient Burden with Sensor-augmented Pump 3.9 -1:00

+1:00

-5:00

Figure 2. CGM record of postprandial control after the dinner.

Treatment Strategies - Diabetes

2.2

It is clear that well-controlled patients need to adjust insulin doses precisely, plan their future activities and keep an eye on their blood glucose at all times. However, these activities consume patient time, psychical resources, limits their freedom, spontaneity and negatively impacts their common daily activities. Nevertheless, patients treated

Treatment Strategies - Glucose Monitoring

with insulin rate their insulin treatment positively. They understand

glucose excursions and enhanced control to range (eCTR) aimed to

that insulin has a positive impact on their long-term health status.14

control glycaemia to the near-normoglycaemia range (3.9-10 mmol/L).

Patients using modern technologies like sensor-augmented pumps

All subjects were hospitalised for 22 hours and their regimen included

pay more attention to their diabetes care then patients on multiple

meals, overnight rest and 30 minutes of exercise. sCTR increased the

daily injections. Patients on pumps and sensors spent an extra 2 hours

time in near normoglycaemia from 61 to 74%, while the time spent in

per week on diabetes-related care during pump initiation and an extra

hypoglycaemia was reduced. Glycaemic variability was reduced

1 hour per week after initiation than the patients on MDI. Despite

overnight. eCTR improved mean blood glucose from 7.7 to 6.7 mmol/L

patients and caregivers reporting satisfaction with SAP treatment

without increasing hypoglycemia. Patients in eCTR settings reached

(related to a therapeutic efficacy, convenience and level of interference

97% time in near normoglycaemia and 77% time in the optimal

with daily activities) in the STAR 3 trial,16 some patients exhibited

glycaemic control.

symptoms of burn-out: lifestyle non-adherence, omitting SMBG, sensor use and sometimes also insulin treatment. In the INTEPRET study,

Low Glucose Suspend

patients used glucose sensor for 37% in the first 3 months of the 1-year

Currently, there is only one feature of the close-loop implemented in

follow-up compared to 27% in the 3 last months.6 As was shown by

a commercially available device. The low glucose suspend function is

Beck et al. and confirmed in the meta-analysis of Pickup et al., the

an optional tool in the insulin pump for a temporary discontinuation

efficacy of CGM or SAP is positively associated with the time spent on

of insulin delivery in a case when the hypoglycaemic alarm is not

the sensor.

responded by the patient. Insulin delivery is restarted after two

7, 11

The loss of patientsâ&#x20AC;&#x2122; adherence to the sensor use is

therefore alarming.

hours to prevent rebound hyperglycaemia. The use of low glucose suspend function was associated with a reduction of hypoglycaemia

Current Advances in Closed-loop Systems

in children and adolescents in a real-life setting.21 It also reduced

Previous studies have shown that closed-loop systems are feasible, at

nocturnal hypoglycaemia in high-risk adult Type 1 diabetic

least when the glycaemic control is not disturbed by food intake or

patients.22 Moreover, this function was well-accepted and rated by

exercise. Closed-loop systems were used overnight with promising

these adult patients.

results in children with Type 1 diabetes.17, 18 However, the ultimate challenge for the closed-loops system is represented by careless

Conclusions

operation, independent of the patientâ&#x20AC;&#x2122;s food intake and physical

Patients with Type 1 diabetes have a profit from frequent monitoring of

activity. Recent results of a 36-hours uninterrupted closed-loop basal

their blood glucose. Awareness of their glycaemia facilitates their

insulin delivery (2 nights and one day) in 12 adolescent Type 1 diabetes

qualified decision about the optimal dose of insulin. Continuous

published by Elleri et al. showed excellent data from this point of view.

glucose monitoring is a useful tool for better self-management of the

Patients applied boluses before main meals but not before snacks.

patients. However, it still does not prevent natural burn-out of diabetic

They were also exposed to moderate exercise under controlled

patients resulting from the necessary attention paid to the glucose

conditions twice a day that was not announced to the control

values and insulin adjustments. Closed-loop systems are feasible at this

algorithm. The percentage time spent in the target range was

moment and the first results from clinical studies attempting to model

increased by closed-loop insulin delivery to 84% (vs. 49% during the

a real-life situation (daytime, food and exercise) show excellent efficacy.

control visit). In 17 of 24 nights during closed-loop insulin delivery

However, it will take some time and thorough testing of efficacy and

patients reached 100% time spent in the target range. Nine

safety before these systems will reach commercial availability. Low

hypoglycaemic events (5 of them related to exercise) were observed

glucose suspend of the insulin pump, the first commercially available

during closed-loop test comparable to the control visit (10 events).19 In

and commonly used feature based on the closed loop, reduces

another study involving 11 adolescents and 27 adults published by

hypoglycaemia and is well-accepted by the patients. It may suggest

Breton et al.,20 the authors tested two modular closed-loop attitudes.

how the fully functional closed-loop systems will be welcomed by the

Standard control to range (sCTR) was designed to prevent extreme

patients and helpful in reducing the diabetes burden.

References 1. Miller, K.M., Beck, R.W., Bergenstal, R.M. et al.: Evidence of a Strong Association Between Frequency of SelfMonitoring of Blood Glucose and Hemoglobin A1C Levels in T1D Exchange Clinic Registry Participants. Diabetes Care, 2013. 2. Cryer, P.E.: Hypoglycemia: still the limiting factor in the glycemic management of diabetes. Endocr Pract, 2008. 14(6): p. 750-6. 3. Cryer, P.E.: Severe hypoglycemia predicts mortality in diabetes. Diabetes Care, 2012. 35(9): p. 1814-6. 4. Nixon, R. and Pickup, J.C.: Fear of hypoglycemia in type 1 diabetes managed by continuous subcutaneous

insulin infusion: is it associated with poor glycemic control? Diabetes Technol Ther, 2011. 13(2): p. 93-8. 5. Schmidt, S. and Norgaard, K.: Sensor-augmented pump therapy at 36 months. Diabetes Technol Ther, 2012. 14(12): p. 1174-7. 6. Norgaard, K., Scaramuzza, A., Bratina, N. et al.: Routine Sensor-Augmented Pump Therapy in Type 1 Diabetes: The INTERPRET Study. Diabetes Technol Ther, 2013. 15(4): p. 273-80. 7. Pickup, J.C., Freeman, S.C., and Sutton, A.J.: Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with

self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. BMJ, 2011. 343: p. d3805. 8. Battelino, T., Phillip, M., Bratina, N. et al.: Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care, 2011. 34(4): p. 795-800. 9. Buckingham, B., Wilson, D.M., Lecher, T. et al.: Duration of nocturnal hypoglycemia before seizures. Diabetes Care, 2008. 31(11): p. 2110-2. 10. Buse, J.B., Kudva, Y.C., Battelino, T. et al.: Effects of sensor-augmented pump therapy on glycemic variability in well-controlled type 1 diabetes in the STAR Treatment Strategies - Diabetes

Treatment Strategies - Glucose Monitoring

3 study. Diabetes Technol Ther, 2012. 14(7): p. 644-7. 11. Beck, R.W., Buckingham, B., Miller, K. et al.: Factors Predictive of Use and of Benefit From Continuous Glucose Monitoring in Type 1 Diabetes. Diabetes Care, 2009. 32(11): p. 1947-1953. 12. Langendam, M., Luijf, Y.M., Hooft, L. et al.: Continuous glucose monitoring systems for type 1 diabetes mellitus. Cochrane Database Syst Rev, 2012. 1: p. CD008101. 13. Bergenstal, R.M., Tamborlane, W.V., Ahmann, A. et al.: Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med, 2010. 363(4): p. 311-20. 14. Peyrot, M., Barnett, A.H., Meneghini, L.F. et al.: Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study. Diabet Med, 2012. 29(5): p. 682-9. 15. Kamble, S., Weinfurt, K.P., Schulman, K.A. et al.:

Treatment Strategies - Diabetes

Patient Time Costs Associated with Sensor-Augmented Insulin Pump Therapy for Type 1 Diabetes: Results from the STAR 3 Randomized Trial. Med Decis Making, 2013. 33(2): p. 215-24. 16. Peyrot, M., Rubin, R.R., and Group, S.S.: Treatment satisfaction in the Sensor-Augmented Pump Therapy for A1C Reduction 3 (STAR 3) trial. Diabet Med, 2013. 30(4): p. 464-7. 17. Elleri, D., Allen, J.M., Biagioni, M. et al.: Evaluation of a portable ambulatory prototype for automated overnight closed-loop insulin delivery in young people with type 1 diabetes. Pediatr Diabetes, 2012. 13(6): p. 449-53. 18. Kumareswaran, K., Elleri, D., Allen, J.M. et al.: Meta-analysis of overnight closed-loop randomized studies in children and adults with type 1 diabetes: the Cambridge cohort. J Diabetes Sci Technol, 2011. 5(6): p. 1352-62.

19. Elleri, D., Allen, J.M., Kumareswaran, K. et al.: Closed-Loop Basal Insulin Delivery Over 36 Hours in Adolescents With Type 1 Diabetes: Randomized clinical trial. Diabetes Care, 2013. 36(4): p. 838-44. 20. Breton, M., Farret, A., Bruttomesso, D. et al.: Fully integrated artificial pancreas in type 1 diabetes: modular closed-loop glucose control maintains near normoglycemia. Diabetes, 2012. 61(9): p. 2230-7. 21. Danne, T., Kordonouri, O., Holder, M. et al.: Prevention of hypoglycemia by using low glucose suspend function in sensor-augmented pump therapy. Diabetes Technol Ther, 2011. 13(11): p. 1129-34. 22. Choudhary, P., Shin, J., Wang, Y. et al.: Insulin pump therapy with automated insulin suspension in response to hypoglycemia: reduction in nocturnal hypoglycemia in those at greatest risk. Diabetes Care, 2011. 34(9): p. 2023-5.

Treatment Strategies - Further Reading

Further Reading Please see the abstracts below for further reading on glucose monitoring. These articles plus others are available in previous editions of Treatment Strategies - Diabetes. Please see our website for more articles on glucose monitoring and a range of other topics within diabetes.

Monitoring, Assessment, and Control of Blood Glucose Fluctuations in Diabetes Boris P. Kovatchev Professor, Department of Psychiatry and Neurobehavioral Sciences and Department of Systems and Information Engineering, Director, Center for Diabetes Technology, University of Virginia, Charlottesville, Virginia

iabetes is a complex of disorders, characterised by a

control without increasing their risk for hypoglycaemia. However,

common final element of hyperglycaemia. Intensive

the struggle for tight glycemic control could result in large blood

treatment with insulin and with oral medication to

glucose (BG) fluctuations over time. This process is influenced by

maintain nearly normal levels of glycaemia markedly reduces

many external factors, including the timing and amount of insulin

chronic complications in both type 1 and type 2 diabetes mellitus

injected, food eaten, physical activity, etc. In other words, BG

(T1DM, T2DM), but may risk symptomatic hypoglycaemia and

fluctuations in diabetes are the measurable result of the action

potentially life-threatening severe hypoglycaemia. Therefore,

of a complex dynamical system, influenced by many internal and

hypoglycaemia has been identified as the primary barrier to

external factors. This article looks at different methods of glucose

optimal diabetes management. Thus, people with T1DM and T2DM monitoring, including the artificial pancreas, self-monitoring and face a life long optimisation problem: to maintain strict glycaemic

continuous glucose monitoring.

Continuous Glucose Monitoring Pratik Choudhary Senior Lecturer and Consultant in Diabetes, Department of Diabetes, King’s College London

ost patients with type 1 and insulin treated type 2 diabetes

in those with impaired awareness is emerging, as is the value of

test their capillary blood glucose multiple times a day

this technology in managing pregnancy in diabetes. However, the

and base decisions about food intake and insulin dose

promise of continuous glucose monitoring extends beyond the

adjustment on these results. These capillary readings only provide

current applications with alarms and real- time displays. It paves the

a “snapshot” of information about blood glucose. The advent of

way for the development of closed-loop artificial pancreas systems

continuous glucose monitoring (CGM) has allows patients as well as

that will control insulin delivery on the basis of information obtained

health care providers to gain information about the direction and rate

from the sensors and help patients maintain optimal glycaemic levels

of change of glucose, which can help patients make more appropriate

with minimal if any risk of hypoglycaemia. The first generation of these

decisions. High or low blood glucose alarms can warn them of

devices is already available, which suspends insulin delivery if the

impending glucose excursions, allowing corrective action and helping

patient fails to respond to a hypoglycaemia alarm, and future versions

keep blood glucose concentrations within acceptable limits.

that control blood glucose overnight are in advanced stages of testing.

CGM has been shown to improve glucose control in patients with type

Continuous glucose monitoring has provided a step-change in

1 diabetes without any increase in hypoglycaemia. There have been

diabetes management, just as home glucose monitoring did three

demonstrable improvements in quality of life, particularly in fear of

decades previously, and will help many more patients gain control

hypoglycaemia. Data on the ability of CGM to reduce hypoglycaemia

over their diabetes.

Treatment Strategies - Diabetes

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Treatment Strategies - Type 1 Diabetes

Enteroviral Pathogenesis of Type 1 Diabetes: A Role for Enhancing Antibodies? Enagnon Kazali Alidjinou and Didier Hober Laboratory of Virology/EA3610, Faculty of Medicine, University Hospital, University Lille 2, Loos-lez-Lille

Introduction

Cells and Receptors

Type 1 diabetes (T1D) is an autoimmune disease resulting from the loss

CVB can infect a large range of cells. It is generally understood that the

of functional insulin-producing pancreatic islet beta cells. Enteroviruses

virus entry follows the binding to its cellular receptor, the Coxsackie

(EV) belonging to the Picornaviridae family, and especially

and Adenovirus Receptor (CAR). The most common process to CVB

Coxsackievirus B (CVB), are thought to strongly contribute to the

internalisation into cells is similar to macropinocytosis. However,

multifactorial process leading to the development of T1D. Although it

several findings indicated that the mechanism of the entry of CVB into

is well known that the disease results from an autoimmune destruction

the cell depends on the cell type. Indeed, CVB can enter in cells that

of pancreatic beta cells, the role of CVB in the process is not entirely clear,

express Fc receptors (e.g. those of the immune system, such as

even if various mechanisms have been reported.3-5 During a viral

macrophages, monocytes, B-cells and granulocytes), when bound to

infection, enhancing antibodies in contrast to neutralising antibodies

CVB-specific antibodies.8 This virus entry, dependant on FcR, is the

can play a potentiating role and increase the infectivity of target cells.

most described of ADE mechanisms. In this scenario, immune

The antibody-dependent enhancement (ADE) of the infection has been

complexes constituted by virus-bound antibodies recognise at least

reported for various viruses. The ADE of the infection can then contribute

one of the receptors for the Fc part of antibodies on the cell surface,

to the pathogenesis of virus-induced diseases.

providing a bridge that enhances the attachment of viruses to the

1-4

6, 7

cells.6, 7 The ADE phenomenon has been described with various viruses In this chapter, the mechanism of the ADE of CVB infection will be

that replicate in monocytes and macrophages.9 Using peripheral blood

described; and its implications on the role of CVB in the pathogenesis

mononuclear cells, it was shown that CD14+ monocytes were target

of T1D will be analysed.

cells in the ADE of CVB4 infection.10 The ADE of CVB infection was also observed in murine macrophagic cell lines J774.1 and P388D1.11

The Antibody-dependent Enhancement of CVB Infection

Previous studies by our team reported that the ADE was dependent on

Enhancement of viral infectivity by antiviral antibodies depends

Receptor), the cellular receptor of CVB, was also needed,10-12 unlike

beyond the virus, on the quality and quantity of several factors

some viruses for which ADE enables emancipation from their cellular

including target cells and antibodies.

receptor for infection. For these viruses, primary non-susceptible cells

FcγRII and FcγRIII. In addition, CAR (Coxsackie and Adenovirus

could then be infected if they express Fc receptors.7 Enagnon Kazali Alidjinou is a former Resident in Medical Biology specialising in virology. He is Assistant in the Department of Virology at Regional and Universitary Hospital Center of Lille and he is preparing a PhD in Virology in the Laboratory of Virology/EA 3610, University Lille 2.

Antibodies Several factors such as the class, the concentration and the epitope specificity of the antibody seem to be essential for ADE of CVB4 infection. Antibodies involved in the facilitation of CVB4 infection have been identified as IgG antibodies directed against VP4, a viral capsid

Didier Hober is Professor of Virology at the Faculty of Medicine in Lille. He is Director of Laboratory of Virology/EA 3610: Viral pathogenesis of type 1 diabetes at University Lille 2. He is also Head of the Department of Virology at Regional and Universitary Hospital Center of Lille.

protein. The target amino acid sequence of these antibodies was shown to be localised between amino acids 11 and 30 of the VP4 protein (69 amino acids in total).13, 14 According to X-ray crystallography datas obtained at – 196°C, VP4 is buried in the capsid and is not accessible at the virion surface; however it is thought that in physiological conditions, conformational changes may expose a part of this protein, making it Treatment Strategies - Diabetes

Treatment Strategies - Type 1 Diabetes

Enteroviral infection by fecal-oral route Replication in the intestine

Systemic infection

ADE: virus spreading FCγR CAR Pancreas IFNα ADE: potentiating viral persistance and bystander activation in pancreas Cytotoxic T Lymphocytes Autorective T Lymphocytes Beta cells

Beta cells damaging and type 1 diabetes development

Figure 1. Role of enhancing antibodies in the enteroviral pathogenesis of Type 1 diabetes. The enteroviruses are transmitted by an oral route. After primary replication in the intestine, the viruses can spread to the circulation and to target organs such as the pancreas. The antibody dependent enhancement (ADE) of the infection can amplify the replication and the dissemination of the viruses. In the pancreas of subjects with a genetic predisposition, the ADE of enteroviruses infection can damage beta cells through two possible mechanisms: the persistance and the bystander activation of an autoimmune destruction of beta cells.

recognisable by enhancing antibodies. Enhancing antibodies against

enhances the viral replication.9 The results of the facilitation of CVB

VP4 protein also seem to be type-specific because no cross reaction was

infection have been described in the literature through studies using

observed between CVB3 and CVB4.

cell culture systems and animal models, and a link has been strongly

suspected with T1D development in humans. Moreover, studies using plasma or serum for ADE demonstrated that facilitation was observed at higher dilutions. Indeed, it was reported

Effects of Enhancement of CVB Infection

that at sub-neutralising concentrations, the infection may be

Our group early reported the effects of facilitation of CVB infection

enhanced. At high concentrations of neutralising antibodies most of

using monocyte-enriched peripheral blood mononuclear cells (PBMC).

the binding sites of the virion are blocked, while in sub-neutralising

It was clearly demonstrated that incubation of CVB with diluted plasma

conditions, available Fc portion of a neutralising antibody on one side

or non-neutralising anti-CVB4 IgG antibodies before inoculation to

and unoccupied viral proteins on the other side may allow

PBMC resulted in a production of high amounts of interferon α (IFNα)

enhancement of infectivity. Nevertheless, assuming that enhancing

while inoculation of the virus alone led to a very weak production of

antibodies are different from neutralising ones, with different epitopes,

IFNα. This enhanced production of IFNα is undoubtedly linked to an

it is conceivable that at low concentrations of neutralising antibodies,

increase of CVB infection as shown by viral RNA and protein detection

epitopes of enhancing antibodies are further exposed.

in cells.10, 12

ADE of CVB Infection as a Possible Mechanism Involved in the Pathogenesis of T1D

Similar results were obtained using the THP-1 monocytic-like cell line

6, 7

which expresses FcγR I, II and III receptors.15

The ADE of a viral infection does not only facilitate virus entry but also modifies innate and adaptive intracellular antiviral mechanisms and 66

Treatment Strategies - Diabetes

The effects of the facilitation of CVB infection by antibodies were also

Treatment Strategies - Type 1 Diabetes

evaluated in vivo. Enhancement of CVB3 infection in A/J male mice

patients were inoculated with CVB4, higher amounts of IFNα were

were observed following inoculation of the virus in presence of

detected in the culture supernatant fluid of cells from diabetic patients.20

anti-CVB2 IgG antibodies. An increase of up to 1000-fold of the viral

Moreover, anti-VP4 antibodies which were shown to be involved in the

load was noted in blood and in target organs such as the heart,

ADE of CVB4 infection were found more frequently and at higher

pancreas, and spleen. Worsen histopathologic aspects were also

concentrations among diabetic subjects.21

observed in the exocrine pancreas and in the heart.11 Experiments by Kishimoto et al. on C3H/He male mice were also very conclusive. After a

• The enhancement of CVB infection is involved in the process leading

first immunisation with CVB3, the second inoculation yielded different

to the destruction or the damaging of pancreatic beta cells.

results according to the titer of anti-CVB3 antibodies in mice. While mice with high titers of anti-CVB3 antibodies were fully protected from

The pancreas is a main target for enteroviruses. Many strains of CVB are

the myocarditic strain of CVB3, those without anti-CVB3 antibodies

naturally pancreatotropic or can become pancreatotropic through

presented a moderate myocarditis with a slight T cell and macrophagic

adaptation to pancreatic tissue.22, 23 Enterovirus components were

infiltration in the myocardium, which was accompanied by moderate

detected in pancreas biopsy samples of diabetic subjects and

viral titers and by a weak increase in the concentration of the

especially in islets beta cells.24, 25

chemoattractive cytokine MIP-2 in blood. In mice with weak titers of anti-CVB3 antibodies, the inoculation of CVB3 resulted in an

Several mechanisms have been proposed to explain the role of CVB in

exacerbated and sometimes lethal myocarditis with a strong T cell and

the alteration of pancreatic beta cells. ADE of CVB infection is thought

macrophagic infiltration in the myocardium, which was accompanied

to potentially contribute to two of these hypotheses - the ‘viral

by elevated viral titers in this organ and a marked increase in the

persistance’ and the ‘bystander activation’.

concentration of MIP-2 in blood.16 An enhanced infection of monocytes, macrophages and other immune

Suggested Scenario for the Role of Enhancing Antibodies in

cells with CVB which can result in an increased and possibly continuous

the Enteroviral Pathogenesis of T1D

virus production may play a role in the infection of beta cells and in the

The outcome of a viral infection depends on the virus and the host

persistence of CVB in these cells. Thus, the infection of beta cells can

factors, namely the immune system; and this interplay is well

damage or disturb these cells, and may contribute to an activation of

demonstrated by the ADE phenomenon. The results of ADE in vivo can

immune system by prolonged presentation of viral antigens and self

be an escape from immune system and an increase of infectivity in the

antigens to T lymphocytes.26 On the other hand, the bystander

target organ, but it can also amplify the immune response.6, 7 Based on

activation is a scenario in which enterovirus infection could induce a

the previous reports on ADE of CVB infection and given that numerous

very important local inflammation in beta cells with an increased

studies have shown a more frequent detection of CVB in type 1

expression of stress markers, phagocytosis and self-antigens

diabetic patients, it is highly tempting to suspect the enhancement of

presentation.27 The inflammation is deleterious by itself to beta cells as

CVB infection as a mechanism contributing to induce or to aggravate

shown by in vitro experiments and studies in animals;28 but will also

T1D. This issue will be addressed through two hypotheses:

promote recruitment and activation of existing autoreactive T cells. The ADE, by potentiating the immune response, can aggravate these

• The enhancement of CVB infection can contribute to the spreading

effects leading to damage of pancreatic islets.

of virus in the body and especially in the pancreas.

Conclusion After transmission by faecal-oral route, the primary replication of CVB

There are abundant data in the literature supporting a role for

occurs in the intestine. The detection of enterovirus in the mucosa of small

enteroviruses, and especially CVB, as an environmental factor in the

intestine of T1D patients has been reported.17, 18 From the gut, a systemic

development of T1D, at least in some genetically susceptible individuals.

infection can lead to dissemination of the virus to other target organs. In

However the molecular mechanisms of the enteroviral pathogenesis of

developed countries where T1D incidence is rapidly increasing, there is a

the disease are still fuelling debate. In so far as the ADE of CVB infection

decrease in the prevalence of enterovirus infection. This low prevalence of

can amplify the effects of the virus in vitro and in vivo, this process may

enteroviral infections in rich areas results in low levels of anti-enterovirus

play a role in the complex relationship between enteroviruses and T1D.

antibodies in the population. The picture is then compatible with a

Further studies are needed to investigate this hypothesis.

favourable situation to ADE, as described above. Data from studies in humans also suggested such association. IFNα, which was shown to be a

Acknowledgements

marker of ADE of CVB in vitro, was detected more frequently and at higher

The authors would like to thank all of their collaborators. This work was

levels in the blood of diabetic patients than in the blood of healthy

supported by the Ministère de l’Education Nationale de la Recherche et

individuals,19 and enteroviral RNA was present in the blood of patients

de la Technologie, Université Lille 2 (UPRES EA3610), and CHRU Lille,

with detectable IFNα. When whole blood or PBMC from diabetic or healthy

and by the EU FP7 (GA-261441-PEVNET). Treatment Strategies - Diabetes

Treatment Strategies - Type 1 Diabetes

References 1. Hober D, Alidjinou EK, “Enteroviral pathogenesis of type 1 diabetes: queries and answers“, Curr. Opin. Infect. Dis. (2013), 26(3):263-9. 2. Yeung WC, Rawlinson WD, Craig ME, “Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies”, BMJ (2011), 342:d35. 3. Hober D, Sauter P, “Pathogenesis of type 1 diabetes mellitus: interplay between enterovirus and host”, Nat. Rev. Endocrinol. (2010), 6: 279–89. 4. Hober D, Sane F, “Enteroviruses and type 1 diabetes”, BMJ (2011), 342: c7072. 5. Lind K, Hühn MH, Flodström-Tullberg M, “Immunology in the clinic review series; focus on type 1 diabetes and viruses: the innate immune response to enteroviruses and its possible role in regulating type 1 diabetes”, Clin. Exp. Immunol. (2012), 168: 30–8. 6. Takada A, Kawaoka Y, “Antibody-dependent enhancement of viral infection: molecular mechanisms and in vivo implications”, Rev. Med. Virol. (2003), 13: 387–398 7. Sauter P, Hober D, “Mechanisms and results of the antibodydependent enhancement of viral infections and role in the pathogenesis of coxsackievirus B-induced diseases”, Microbes Infect. (2009), 11: 443–51. 8. Kemball CC, Alirezaei M, Whitton JL, “Type B coxsackieviruses and their interactions with the innate and adaptive immune systems”, Future Microbiol. (2010), 5(9): 1329-47. 9. Halstead SB, Mahalingam S, Marovich MA, et al., “Intrinsic antibody-dependent enhancement of microbial infection in macrophages: disease regulation by immune complexes”, Lancet Infect. Dis. (2010), 10(10): 712-22. 10. Hober D, Chehadeh W, Bouzidi A, et al., “Antibodydependent enhancement of coxsackievirus B4

Treatment Strategies - Diabetes

infectivity of human peripheral blood mononuclear cells results in increased interferon-alpha synthesis”, J. Infect. Dis. (2001), 184: 1098–108. 11. Girn J, Kavoosi M, Chantler J, “Enhancement of coxsackievirus B3 infection by antibody to a different coxsackievirus strain”, J. Gen. Virol. (2002), 83: 351–8. 12. Chehadeh W, Bouzidi A, Alm G, et al., “Human antibodies isolated from plasma by affinity chromatography increase the coxsackievirus B4induced synthesis of interferon-alpha by human peripheral blood mononuclear cells in vitro”, J. Gen. Virol. (2001), 82: 1899–907. 13. Chehadeh W, Lobert PE, Sauter P et al., “Viral protein VP4 is a target of human antibodies enhancing coxsackievirus B4- and B3-induced synthesis of alpha interferon”, J. Virol. (2005), 79: 13882– 91. 14. Sauter P, Lobert PE, Lucas B et al., “Role of the capsid protein VP4 in the plasma-dependent enhancement of the Coxsackievirus B4E2- infection of human peripheral blood cells”, Virus Res. (2007), 125: 183–90. 15. Goffard A, Alidjinou EK, Sané F, et al., “Antibodies enhance the infection of phorbol-ester-differentiated human monocyte-like cells with coxsackievirus B4”, Microbes Infect. (2013), 15(1): 18-27. 16. Kishimoto C, Kurokawa M, Ochiai H, “Antibodymediated immune enhancement in coxsackievirus B3 myocarditis”, J. Mol. Cell. Cardiol. (2002), 34: 1227–38. 17. Oikarinen M, Tauriainen S, Honkanen T, et al., “Detection of enteroviruses in the intestine of type 1 diabetic patients“, Clin. Exp. Immunol. (2008), 151 (1): 71–75. 18. Oikarinen M, Tauriainen S, Oikarinen S, et al., “Type 1 diabetes is associated with enterovirus infection in gut mucosa”, Diabetes (2012), 61(3): 687-91. 19. Chehadeh W, Weill J, Vantyghem MC et al., “Increased level of interferon-alpha in blood of

patients with insulin-dependent diabetes mellitus: relationship with coxsackievirus B infection”, J. Infect. Dis. (2000), 181: 1929–39. 20. Hober D, Chehadeh W, Weill J et al., “Circulating and cell-bound antibodies increase coxsackievirus B4-induced production of IFN alpha by peripheral blood mononuclear cells from patients with type 1 diabetes”, J. Gen. Virol. (2002), 83: 2169–76. 21. Sauter P, Chehadeh W, Lobert PE et al., “A part of the VP4 capsid protein exhibited by coxsackievirus B4 E2 is the target of antibodies contained in plasma from patients with type 1 diabetes”, J. Med. Virol. (2008), 80: 866–78. 22. Hyoty H, “Enterovirus infections and type 1 diabetes”, Ann. Med. (2002), 34: 138–47. 23. Jaïdane H, Sane F, Gharbi J, et al., “Coxsackievirus B4 and type 1 diabetes pathogenesis: contribution of animal models”, Diabetes Metab. Res. Rev. (2009), 25: 591–603. 24. Dotta F, Censini S, van Halteren A, et al., “Coxsackie B4 virus infection of cells and natural killer cell insulitis in recent-onset type 1 diabetic patients”, Proc. Natl. Acad. Sci. (2007), 104:5115. 25. Richardson S, Willcox A, Bone A, et al., “The prevalence of enteroviral capsid protein vp1 immunostaining in pancreatic islets in human type 1 diabetes”, Diabetologia (2009), 52: 1143-51. 26. Jaïdane H, Sauter P, Sane F, et al., “Enteroviruses and type 1 diabetes: towards a better understanding of the relationship”, Rev. Med. Virol. (2010), 20: 265–80. 27. Richer MJ, Horwitz MS, “Coxsackievirus infection as an environmental factor in the etiology of type 1 diabetes”, Autoimmun. Rev. (2009), 8: 611 – 615. 28. Donath MY, Størling J, Berchtold LA, et al., “Cytokines and beta-cell biology: from concept to clinical translation”, Endocr. Rev. (2008), 29: 334 – 350.

Treatment Strategies - Type 1 Diabetes

Challenges in Estimating Glomerular Filtration Rate in Diabetic Patients Marijana Vučić Lovrenčić Department of Laboratory Medicine, Clinical Institute of Medical Biochemistry and Laboratory Medicine, Merkur Teaching Hospital, Zagreb

Introduction

Current guidelines regarding diabetic nephropathy screening include

The prevalence of diabetes mellitus, as well as diabetes-related

the testing of urinary albumin excretion and the measurement of serum

complications is increasing worldwide. Diabetic nephropathy has

creatinine in all adults with diabetes regardless of the degree of urine

become the most common single cause of end-stage renal disease,

albumin excretion.2 The serum creatinine should be used to estimate

seriously affecting both patient outcomes and economical resources of

GFR and stage the level of chronic kidney disease (CKD), if present.

healthcare systems. There is a substantial body of evidence which

Current staging of CKD according to GFR values is presented in Table 1.8

emphasises that appropriate intervention (intensive diabetes and hypertension management) at an early stage of diabetic nephropathy

Glomerular Filtration Rate Assessment

can significantly improve the outcomes for diabetic patients. Thus,

An ideal marker of glomerular filtration is a physiologically inert, not

screening for chronic kidney disease in asymptomatic patients remains

protein-bound molecule that is freely filtered by the glomeruli, not

one of the most important tasks in diabetes management.

secreted by the tubuli, and not synthetised, transported or metabolised

3, 4

by the kidney.9 Among the very few substances fulfilling these criteria, a Urinary albumin excretion rate within range 30-299 mg/24h

plant polysaccharide inulin is considered to be the gold standard,

(“microalbuminuria“) has been identified as a sensitive marker of

whereas a radiograhic contrast iohexole and various radionuclides

glomerular basal membrane damage at an early stage of diabetic

(125I-iothalamate, 51Cr-EDTA or 99mTc-DTPA) represent some suitable

nephropathy. However, despite the fact that screening for

alternatives. These procedures are complex, costly, time- and labour-

microalbuminuria had been the recommended procedure in diabetes

consuming, and involve exogenous administration of substances and

care for many years, undiagnosed chronic kidney disease is still

the collection of samples followed by the appropriate analytical

common in diabetes.

quantitation of the applied marker. Furthermore, measurement of GFR

5, 6

There is an accumulating body of evidence

which suggests that a significant loss of kidney function, assessed as

by either of the procedures may suffer from inaccuracies related to

glomerular filtration rate (GFR) decline is not uncommon in diabetic

specimen collection protocols, and different procedures may yield

patients without overt albuminuria, implicating a complementary,

substantially different results. Consequently, glomerular filtration rate

rather than consecutive relationship between renal function

measurement is not a suitable tool for the routine assessment of kidney

impairment and glomerular membrane damage in the pathogenesis

function and screening for chronic kidney disease.

of diabetic kidney disease.

5, 7

Serum creatinine has been used as a marker of kidney function for many Marijana Vučić Lovrenčić, Head of the Department of Laboratory Medicine at the Merkur Teaching Hospital in Zagreb, is a specialist in medical biochemistry and laboratory medicine with a PhD degree in biomedical sciences from the University of Zagreb, Croatia. Her primary focus of both her professional and scientific interest lies in the laboratory medicine associated to the diagnosis and management of diabetes mellitus and endocrine disorders. Her scientific bibliography (http://bib.irb.hr/lista-radova?autor=176744) involves original papers, bookchapters and congress-abstracts, and her professional activities resulted into successful implementation of global guidelines regarding key laboratory tests supporting clinical diabetology to the National Medical Laboratory Practice. She is a member of the EASD, AACC (American Association of Clinical Chemistry) and CCMB (Croatian Chambers of Medical Biochemistry).

years due to practical reasons, despite serious drawbacks originating from both biological and analytical limitations.10 Being significantly influenced by nutrition habits, muscular mass, age, gender and ethnicity, and partially secreted and reabsorbed by the tubuli, creatinine is far from an ideal marker of glomerular filtration. While intra-individual variability of creatinine is low (5.3%), reference intervals are relatively wide, and a significant loss of kidney function may occur in many individuals whose creatinine levels are still well within reference intervals.9, 10 Moreover, the clinical reliability of creatinine has been burdened with analytical issues, particularly non-specificity of the most commonly used Jaffe alkaline picrate method and a lack of standardisation. Recent efforts regarding Treatment Strategies - Diabetes

Treatment Strategies - Type 1 Diabetes

from serum creatinine adjusted for age and weight was published by

GFR

GFR (ml/min/1.73 m2)

Classification

Cockroft and Gault in 1976 (C-G equation,13). The equation was derived

≥ 90

Normal or high

and validated in a population of hospitalised patients, mostly males.

60-89

Mildly decreased

G3a

45-59

Mildly to moderately decreased

G3b

30-44

severely decreased

these limitations, the potential to estimate GFR by a relatively simple

15-29

Severely decreased

calculation from serum creatinine and anthropometric measures

<15

Kidney failure